NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of Selected Vegetables/Sun’s Soup as a treatment for people with cancer. The summary includes a brief history of Selected Vegetables/Sun’s Soup and a review of animal and human studies. The information in the Human/Clinical Studies section is summarized in a table located at the end of that section.

This summary contains the following key information:

Many of the medical and scientific terms used in the summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

“Selected Vegetables” and “Sun’s Soup” are names given to several different mixtures of vegetables and herbs that have been studied as treatments for cancer and other medical conditions, including acquired immunodeficiency syndrome.[1,2] The original formulation contained shiitake mushroom (Lentinus edodes [Berk.] Singer), mung bean (Phaseolus radiatus L.), Hedyotis diffusa Willd. (also known by the Chinese herbal name Bai Hua She She Cao), and barbat skullcap (Scutellaria barbata D. Don, also known by the Chinese herbal name Ban Zhi Lian).

A second formulation, specifically named “Selected Vegetables” (“SV”), was tested in a phase I/II clinical trial that involved patients with advanced non-small cell lung cancer (refer to the Human/Clinical Studies section of this summary for more information).[1]

A third formulation, called “Frozen SV” or “FSV,” has also been studied clinically in patients with advanced non-small cell lung cancer (refer to the Human/Clinical Studies section of this summary for more information).[2]

In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. The FDA can, however, remove from the market dietary supplements that it deems unsafe. It should be noted that no formulation of Selected Vegetables/Sun’s Soup has been approved by the FDA for the treatment of cancer or any other medical condition.

Because dietary supplements are not formally reviewed for manufacturing consistency, there may be considerable variation from lot to lot, and there is no guarantee that ingredients identified on product labels are present in the specified amounts or present at all.

SV/DSV and FSV are reported to contain soybean (Glycine max [L.] Merr.), shiitake mushroom, mung bean, red date (Ziziphus jujuba Miller), scallion (Allium bakeri Regel), garlic (Allium sativum L.), leek (Allium fistulosum L.), lentil (Lens culinaris Medic.), Hawthorn fruit (Crataegus monogyna Jacquin and/or Crataegus oxyacantha L.), onion (Allium cepa L.), ginseng (Panax ginseng C.A. Meyer), Angelica root (Angelica sinensis), licorice (Glycyrrhiza glabra L.), dandelion root (Taraxacum officinale Weber), senega root (Polygala senega L.), ginger (Zingiber officinale Roscoe), olive (Olea europaea L.), sesame seed (Sesamum indicum L.), and parsley (Petroselinum crispum [P. Miller] Nyman ex A.W. Hill).[1,2]

Many of the ingredients in Selected Vegetables/Sun’s Soup were chosen because previous biochemical research and traditional Chinese medicine suggested they contain molecules that have anticancer or immunostimulant activity.[1,2]

Selected Vegetables/Sun’s Soup is administered orally as part of the diet.[1,2] Studies in humans have not always specified a dose or an administration schedule, but daily doses of 30 g SV/DSV, mixed with water or other soup, or of 10 oz (approximately 283 g) FSV were used in the above-mentioned clinical studies in patients with advanced non-small cell lung cancer.[1,2]

To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA. An IND must also be obtained for clinical evaluation of dietary supplements as agents for the treatment or prevention of disease. Because the IND application process is confidential and because the existence of an IND can be disclosed only by the applicants, it is not known whether an IND currently exists for the study of Selected Vegetables/Sun’s Soup as a treatment for cancer or any other disease.

In this summary, the specific formulation of Selected Vegetables/Sun’s Soup given to individual patients or groups of patients will be identified wherever possible.

References

1. Sun AS, Ostadal O, Ryznar V, et al.: Phase I/II study of stage III and IV non-small cell lung cancer patients taking a specific dietary supplement. Nutr Cancer 34 (1): 62-9, 1999. [PUBMED Abstract]
2. Sun AS, Yeh HC, Wang LH, et al.: Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients. Nutr Cancer 39 (1): 85-95, 2001. [PUBMED Abstract]

Selected Vegetables/Sun’s Soup was first conceived as a treatment for cancer in the mid-1980s. In an effort to help a relative who was diagnosed with stage IV non-small cell lung cancer (metastasis to the left adrenal gland), the developer created a mixture that contained shiitake mushroom (Lentinus edodes [Berk.] Singer), mung bean (Phaseolus radiatus L.), Hedyotis diffusa Willd., and barbat skullcap (Scutellaria barbata D. Don) in the belief that these plant materials had anticancer and/or immune-system–stimulating properties. After the relative appeared to benefit from this treatment (the relative was reported to be alive and cancer free for more than 13 years ), three additional patients (one with stage IV kidney cancer that had metastasized to the lungs, one with stage IV kidney cancer that had metastasized to the liver and to the lungs, and one with stage IV non-small cell lung cancer that had metastasized to the brain) were treated with a variant of the original mixture (i.e., a combination of shiitake mushroom and mung bean). (Note: No explanation has been given for the omission of Hedyotis diffusa and barbat skullcap for these patients.) These additional patients were also said to benefit from vegetable/herb treatment. (Refer to the Human/Clinical Studies section of this summary for more information.)

In June 1992, the developer filed a patent application for the “Herbal treatment of malignancy,” and a patent was awarded in August 1995. Also in June 1992, the developer initiated a clinical trial in the Czech Republic to test Selected Vegetables/Sun’s Soup as a treatment for advanced non-small cell lung cancer.[1] A second clinical study (a nonconsecutive case series) that also involved patients with advanced non-small cell lung cancer was completed in 1997.[2] It is unclear, however, when patient accrual for this second study began.[2] In both reports of the clinical study results, the authors concluded that patients who received Selected Vegetables/Sun’s Soup had prolonged survival.[1,2] (Refer to the Human/Clinical Studies section of this summary for more information.)

As noted previously (refer to the General Information section of this summary for more information), the proposed mechanism of action for Selected Vegetables/Sun’s Soup involves anticancer and/or immune-system–stimulating activities associated with some of the ingredients.[1,2] The following types of compounds likely found in Selected Vegetables/Sun’s Soup have been investigated for these activities: protease inhibitors and autoclave-resistant factors, which are found in soybeans (Glycine max L. Merr.); plant sterols; saponin; inositol hexaphosphate (IP6); beta-glucans; lectins; coumestans such as coumestrol; and isoflavones such as daidzein, genistein, biochanin A, and formononetin.[1,2]

One beta-glucan found in shiitake mushroom (lentinan) has been used as an adjunctive therapy for cancer (primarily gastric cancer and colorectal cancer) in Japan.[3–6] Treatment with lentinan has been reported to prolong the survival of patients with gastric cancer [3–6] and to improve their quality of life.[3] However, lentinan may not be an active component in Selected Vegetables/Sun’s Soup. This compound has a large molecular mass and is believed to have only limited oral bioavailability.[5–7] Therefore, lentinan has usually been given by intravenous injection. Nonetheless, other substances in shiitake mushroom have been identified as having greater oral bioavailability, and these substances have shown anticancer activity in animal experiments.[5,7]

References

1. Sun AS, Ostadal O, Ryznar V, et al.: Phase I/II study of stage III and IV non-small cell lung cancer patients taking a specific dietary supplement. Nutr Cancer 34 (1): 62-9, 1999. [PUBMED Abstract]
2. Sun AS, Yeh HC, Wang LH, et al.: Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients. Nutr Cancer 39 (1): 85-95, 2001. [PUBMED Abstract]
3. Nakano H, Namatame K, Nemoto H, et al.: A multi-institutional prospective study of lentinan in advanced gastric cancer patients with unresectable and recurrent diseases: effect on prolongation of survival and improvement of quality of life. Kanagawa Lentinan Research Group. Hepatogastroenterology 46 (28): 2662-8, 1999 Jul-Aug. [PUBMED Abstract]
4. Taguchi T: Clinical efficacy of lentinan on patients with stomach cancer: end point results of a four-year follow-up survey. Cancer Detect Prev Suppl 1: 333-49, 1987. [PUBMED Abstract]
5. Borchers AT, Stern JS, Hackman RM, et al.: Mushrooms, tumors, and immunity. Proc Soc Exp Biol Med 221 (4): 281-93, 1999. [PUBMED Abstract]
6. Kidd PM: The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev 5 (1): 4-27, 2000. [PUBMED Abstract]
7. Wasser SP, Weis AL: Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: a modern perspective. Crit Rev Immunol 19 (1): 65-96, 1999. [PUBMED Abstract]

Only limited information is available from laboratory or animal studies of Selected Vegetables/Sun’s Soup. The developer’s patent document describes four animal experiments that used two mouse tumor models (mouse sarcoma S1509a, which was used in three of the experiments, and mouse Line 1 lung carcinoma, which was used in one experiment) and that evaluated shiitake mushroom (Lentinus edodes [Berk.] Singer), mung bean (Phaseolus radiatus L.), Hedyotis diffusa Willd., and barbat skullcap (Scutellaria barbata D. Don).

In these experiments, small groups of mice were fed either standard laboratory chow or laboratory chow that had been mixed with one or more of the four named substances. The mice were fed these diets both before and after they received subcutaneous injections of tumor cells. Results presented in the patent document show that tumor growth was slower in mice fed the experimental diets (i.e., containing the substances) than in mice fed standard laboratory chow. However, the greatest inhibition of tumor growth (up to 85% inhibition) was observed in animals fed diets that contained both mung bean and shiitake mushroom.

Results of two additional animal experiments were reported by the developer in a peer-reviewed scientific journal.[1] One experiment was a repetition of the Line 1 lung carcinoma experiment that was described in the developer’s patent document. The results of this experiment were similar to those reported previously: tumor growth was slower in animals fed the experimental diets, with the greatest inhibition of tumor growth (up to 82% inhibition) observed in animals fed a diet that contained both mung bean and shiitake mushroom.

The second experiment also used the Line 1 lung carcinoma tumor model. In this experiment, tumor growth was measured in mice fed either standard laboratory chow or a mixture of standard laboratory chow and DSV (i.e., the commercially available freeze-dried formulation of Selected Vegetables/Sun’s Soup; refer to the General Information section of this summary for more information). Tumor growth was approximately 2.3 times slower (i.e., approximately 65% growth inhibition) in mice fed standard laboratory chow plus DSV than in mice fed standard laboratory chow alone.

References

1. Sun AS, Yeh HC, Wang LH, et al.: Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients. Nutr Cancer 39 (1): 85-95, 2001. [PUBMED Abstract]

The following information is summarized in a table located at the end of this section.

The use of Selected Vegetables/Sun’s Soup as a treatment for human cancer has been investigated in only a limited manner. All available resources—the developer’s patent document and the published reports of two clinical studies [1,2]—have identified fewer than 50 treated patients.

In 1992, the developer initiated a phase I/II clinical trial in the Czech Republic to test Selected Vegetables/Sun’s Soup as a treatment for non-small cell lung cancer.[1,2] The trial included a “toxicity arm” to assess the tolerability of long-term administration of Selected Vegetables/Sun’s Soup and a “survival arm” to assess the mixture’s ability to improve survival in patients with advanced disease. Five patients with stage I cancer were included in the toxicity arm; these patients were treated with conventional therapy (surgery plus radiation therapy or radiation therapy alone) in addition to Selected Vegetables/Sun’s Soup. Nineteen patients with stage III or stage IV disease were included in the survival arm; six of these patients were treated with conventional therapy (radiation therapy alone or chemotherapy alone) in addition to Selected Vegetables/Sun’s Soup, and 13 were treated with conventional therapy (radiation therapy alone, chemotherapy alone, surgery plus radiation therapy, or chemotherapy plus radiation therapy) (12 patients) or best supportive care (one patient) but not Selected Vegetables/Sun’s Soup.

The intended duration of Selected Vegetables/Sun’s Soup treatment for all patients who received the mixture was 24 months. The intended daily dose was 30 g of freeze-dried powder (i.e., DSV; refer to the General Information section of this summary for more information), mixed with water or other soup. Changes in body weight and changes in Karnofsky Performance Status (KPS) were measured in both arms of the trial. Median survival time was the primary endpoint in the survival arm.

In the toxicity arm, all five patients either gained weight or had no change in weight, which was measured twice, i.e., at study entry and 4 to 12 months later. The KPS score, which was also measured twice (at study entry and 3 months later), improved for four of the five patients and remained stable for the fifth. All five individuals were reported to be alive and well 24 months after diagnosis, and none developed a recurrent tumor during follow-up. The actual duration of Selected Vegetables/Sun’s Soup treatment for these patients ranged from more than 17 months to more than 24 months. From these data, the researchers concluded that Selected Vegetables/Sun’s Soup was safe, nontoxic, and well tolerated.[1]

In the survival arm, the average duration of Selected Vegetables/Sun’s Soup treatment was 7.3 months (range, 4–17 months). The median survival time from diagnosis for the six patients who ingested Selected Vegetables/Sun’s Soup was 15.5 months (range, 8 to more than 24 months), compared with a median survival time from diagnosis of 4 months (range, 1–12 months) for the 13 patients in the control group. This difference in median survival time was reported to be statistically significant.[1]

As in the toxicity arm, body weight and KPS were measured twice in the survival arm. Body-weight measurements were made at study entry and at an average of 4.8 months later (range, 3–7 months) for the six patients in the Selected Vegetables/Sun’s Soup treatment group. Among the 13 patients in the control group, nine had weight measurements made at study entry and at an average of 2.6 months later (range, 1–7 months); however, the second body-weight measurements were not available for four control subjects. The average percent body-weight loss for the six patients in the Selected Vegetables/Sun’s Soup treatment group was 2.1%; for the nine patients in the control group, the average percent body-weight loss was 11.6%. This 9.5% difference in body-weight loss was reported to be statistically significant. The two groups of patients had similar average body weights at study entry.[1]

KPS was measured at study entry and again 3 months later for all six patients in the Selected Vegetables/Sun’s Soup treatment group. For the 13 patients in the control group, KPS was measured at study entry and 1 to 3 months later. The first and second KPS scores did not differ substantially for the patients in the Selected Vegetables/Sun’s Soup treatment group. In fact, the second score was higher (indicating an improving condition) for five of the six patients; for the sixth patient, the first and second scores were the same. The second KPS score was lower than the first (indicating a worsening condition) for all 13 patients in the control group. When the average KPS score at study entry for the control subjects was compared with the average score measured 1 to 3 months later, a statistically significant decline in KPS was noted. The average KPS score at study entry for the patients in the control group was not substantially different from the average KPS score at study entry for patients in the Selected Vegetables/Sun’s Soup treatment group.[1]

Although treatment with Selected Vegetables/Sun’s Soup was associated with substantial benefits in this trial, the results cannot be considered conclusive. Several major weaknesses in the design and execution of the trial could have affected the outcome. One major weakness is the small numbers of patients enrolled in the survival arm (six patients in the Selected Vegetables/Sun’s Soup treatment group and 13 in the control group). Larger numbers of patients are needed to obtain reliable results. Another weakness is that the patients in the survival arm were not randomly assigned to the treatment group and the control group. The treatment group consisted of individuals who agreed to be treated with Selected Vegetables/Sun’s Soup; those who refused treatment were assigned to the control group. It is possible that important, unidentified differences existed between patients in the two groups.[1]

In 2001, the developer reported clinical findings for an additional 16 patients who had stage III or stage IV non-small cell lung cancer and who had been treated with Selected Vegetables/Sun’s Soup.[2] The formulation ingested by these patients was Frozen SV, or FSV.[2] Among the 16 patients, 12 consumed FSV for a period of 2 months or more and were considered eligible for analysis. The duration of FSV treatment for these 12 patients ranged from 5 months to more than 46 months. All of the patients were treated with conventional therapy (one or more of the following: surgery, radiation therapy, chemotherapy, or pleurodesis) in addition to treatment with Selected Vegetables/Sun’s Soup.

Among these 12 patients, two had no residual tumor after surgery to remove the primary tumor (n = 1) or surgery to remove the primary tumor and a contralateral lymph node metastasis (n = 1). The patient with the lymph node metastasis consumed FSV for more than 32 months and remained tumor free more than 30 months. This patient survived more than 33 months. The other patient ingested FSV for 14 months and survived 20 months. No information was available concerning the tumor-free period for this second patient.

Among the ten remaining eligible patients, two were reported to have had a complete response to therapy. One of the patients had surgery to remove the primary tumor and then chemotherapy, radiation therapy, and FSV therapy to treat pleural effusion. This patient ingested FSV for 5 months and was still alive at the end of the study period (more than 8 months later). The other patient had surgery to remove the primary tumor, and then radiation therapy and FSV therapy to treat brain and bone metastases. This patient consumed FSV for 16 months and survived 22 months. No information was available about the duration of the tumor-free period for the remaining patient.

Among the eight remaining eligible patients, three had a partial response to treatment, and four had stable or progressive disease. Tumor response data were not available for one eligible patient.

Overall, the median survival time for the 12 eligible patients was 33.5 months, which is substantially longer than the median survival times cited by the developer for historical control subjects (range, 4–15 months).[2] Furthermore, the KPS score, which was measured at the start of FSV treatment and again 5 or more months later, improved for all but one of the eligible patients. On average, the second KPS score was 63% higher than the first score.[2]

As in the case of the phase I/II trial, the results of this nonconsecutive case series should be viewed with caution. Once again, a number of major weaknesses in the design of this clinical study could have influenced its outcome. Among these weaknesses are the following:

With respect to the third point, it is important to note that results obtained with such highly motivated, self-selected patients might not be typical of those obtained with most patients diagnosed with advanced non-small cell lung cancer.

A randomized phase III trial (NCT00246727) of patients with stage IIIB or stage IV non-small cell lung cancer was conducted. The primary objective was to compare the survival of patients receiving Selected Vegetables Sun’s Soup dietary supplement with those receiving a placebo while undergoing treatment with best supportive care (i.e., radiation therapy, surgery, or palliative care).

References

1. Sun AS, Ostadal O, Ryznar V, et al.: Phase I/II study of stage III and IV non-small cell lung cancer patients taking a specific dietary supplement. Nutr Cancer 34 (1): 62-9, 1999. [PUBMED Abstract]
2. Sun AS, Yeh HC, Wang LH, et al.: Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients. Nutr Cancer 39 (1): 85-95, 2001. [PUBMED Abstract]

The only reported adverse effect with the use of Selected Vegetables/Sun’s Soup was a feeling of fullness or bloatedness when freeze-dried Selected Vegetables (SV) was consumed in the amount specified in the phase I/II clinical trial.[1] No adverse effects were reported after ingestion of frozen SV.[2]

References

1. Sun AS, Ostadal O, Ryznar V, et al.: Phase I/II study of stage III and IV non-small cell lung cancer patients taking a specific dietary supplement. Nutr Cancer 34 (1): 62-9, 1999. [PUBMED Abstract]
2. Sun AS, Yeh HC, Wang LH, et al.: Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients. Nutr Cancer 39 (1): 85-95, 2001. [PUBMED Abstract]

Existing data supporting the effectiveness of Selected Vegetables/Sun’s Soup as a treatment for cancer are limited and weak. Only two clinical studies have been reported in the peer-reviewed scientific literature.[1,2] These studies tested the ability of Selected Vegetables/Sun’s Soup to prolong the survival of patients with advanced non-small cell lung cancer. Although ingestion of Selected Vegetables/Sun’s Soup was associated with improved survival in both studies, the results may not be reliable because of the small numbers of patients included in the studies (i.e., a total of 18 evaluable patients) and because of other major weaknesses in the designs of the studies. Different formulations of Selected Vegetables/Sun’s Soup were used in the two studies, making a comparison of the results difficult. Information about the effectiveness of Selected Vegetables/Sun’s Soup as a treatment for other types of cancer is found only in anecdotal reports, and the US Patent 5437866. and no information is available about the safety or the efficacy of this treatment approach in pediatric patients. Additional larger, well-designed clinical studies that test identical formulations of vegetables and herbs are necessary to determine more clearly whether Selected Vegetables/Sun’s Soup can be useful in the treatment of non-small cell lung and other types of cancer.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

References

1. Sun AS, Ostadal O, Ryznar V, et al.: Phase I/II study of stage III and IV non-small cell lung cancer patients taking a specific dietary supplement. Nutr Cancer 34 (1): 62-9, 1999. [PUBMED Abstract]
2. Sun AS, Yeh HC, Wang LH, et al.: Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients. Nutr Cancer 39 (1): 85-95, 2001. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

1. What is Selected Vegetables/Sun’s Soup?

   “Selected Vegetables” and “Sun’s Soup” are names given to several different mixtures of vegetables and herbs that are being studied as treatments for cancer and other medical conditions, including acquired immunodeficiency syndrome (AIDS). The following versions have been used:

   • Original Mixture
     • Shiitake mushroom.
     • Mung beans.
     • Hedyotis diffusa.
     • Scutellaria barbata (barbat skullcap).

     This mixture is not sold in the United States.

   • Freeze-dried Selected Vegetables (DSV), a freeze-dried mixture of vegetables and herbs sold in the United States as a dietary supplement. DSV is reported to contain the following ingredients:
     • Soybean.
     • Shiitake mushroom.
     • Mung bean.
     • Red date.
     • Scallion.
     • Garlic.
     • Leek.
     • Lentils.
     • Hawthorn fruit.
     • Onion.
     • Ginseng.
     • Angelica root.
     • Licorice.
     • Dandelion root.
     • Senega root.
     • Ginger.
     • Olive.
     • Sesame seed.
     • Parsley.
   • Frozen Selected Vegetables (FSV), a frozen mixture of fresh vegetables and herbs, sold in the United States as a dietary supplement. It contains the same vegetables and herbs as in DSV.
2. What is the history of the discovery and use of Selected Vegetables/Sun’s Soup as a complementary and alternative treatment for cancer?

   The vegetable and herb mixture now called Selected Vegetables/Sun’s Soup was developed to treat cancer.

   • In the mid-1980’s, the developer created the mixture to treat a relative who was diagnosed with stage IV non-small cell lung cancer and not helped by standard treatment. The mixture contained shiitake mushroom, mung bean, and the herbs Hedyotis diffusa and barbat skullcap. The developer believed these ingredients contain substances that may block the growth of cancer cells and/or help the body’s immune system attack cancer cells. The relative was reported to be alive and free of cancer more than 13 years later. Three more patients with advanced cancer were treated with a combination of shiitake mushroom and mung bean. These patients were also reported to benefit from the treatment.
   • In 1992, the developer applied for a patent for Selected Vegetables/Sun’s Soup as an herbal treatment of cancer. The developer reported on animal studies done in mice (see Question 5). The developer then began doing clinical trials (see Question 6) to test Selected Vegetables/Sun’s Soup in cancer patients.
   • In 1995, the developer was awarded a patent for Selected Vegetables/Sun’s Soup.

   Many of the vegetables and herbs in Selected Vegetables/Sun’s Soup were chosen because previous research and traditional Chinese medicine suggest they contain anticancer phytochemicals (substances found in plants that may have effects on the body). These include substances such as protease inhibitors, plant sterols, and isoflavones. These ingredients may block the growth of cancer cells and/or improve the way the body’s immune system attacks cancer cells.

3. What is the theory behind the claim that Selected Vegetables/Sun’s Soup is useful in treating cancer?

   The theory is that certain ingredients in Selected Vegetables/Sun’s Soup may contain phytochemicals that have significant anticancer effects in humans. One of these ingredients is shiitake mushroom. Lentinan, which is taken from shiitake mushroom, has been used in Japan to treat stomach and colon cancer after surgery. Treatment with lentinan is reported to help patients with stomach cancer live longer and have a better quality of life. Lentinan may not be easily absorbed by the body from food, so it is usually given by injection. Other substances in shiitake mushroom that are more easily used by the body from food have shown anticancer activity in animal tests.

4. How is Selected Vegetables/Sun’s Soup administered?

   Selected Vegetables/Sun’s Soup is eaten as part of the diet. Daily doses of either 1 ounce of the DSV (mixed with water or other soup) or 10 ounces of the FSV were used in clinical trials.

5. Have any preclinical (laboratory or animal) studies been conducted using Selected Vegetables/Sun’s Soup?

   Few preclinical studies have been done with Selected Vegetables/Sun’s Soup. Research in a laboratory or using animals is done to find out if a drug, procedure, or treatment is likely to be useful in humans. Preclinical studies are done before clinical trials (in humans) are begun.

   A small number of mice were injected with tumor cells and fed either standard food or food mixed with one or more ingredients from Selected Vegetables/Sun’s Soup. The researchers reported that the growth of tumors was slower in the mice that were fed the Selected Vegetables/Sun’s Soup ingredients, compared to the mice that ate standard food. The tumor growth was slowest when the mice were fed both mung bean and shiitake mushroom.

6. Have any clinical trials (research studies with people) of Selected Vegetables/Sun’s Soup been conducted?

   Clinical trials using Selected Vegetables/Sun’s Soup to treat cancer have been done with small numbers of patients. These patients received other types of treatment, either before or during treatment with Selected Vegetables/Sun’s Soup, and different vegetable mixtures were used in the different studies.

   The results of these trials were compared with published information on similar patients who did not receive Selected Vegetables/Sun’s Soup. Most patients receiving the vegetable mixtures lived longer, were better able to carry out their daily activities, and either gained weight or did not lose weight. In some patients who ate Selected Vegetables/Sun’s Soup, tumor growth slowed or the tumor completely went away. Because patients in these trials received other treatments, it is not known if their responses were caused by Selected Vegetables/Sun’s Soup, the other treatments, or both. None of the trials were randomized or controlled. Randomized clinical trials give the highest level of evidence. In randomized trials, volunteers are put randomly (by chance) into one of 2 or more groups that compare different treatments. In a controlled trial, one group (called the control group) does not receive the new treatment being studied. The control group is then compared to the groups that receive the new treatment, to see if the new treatment works. Randomized controlled trials, enrolling larger numbers of people, are needed to confirm the results of studies done so far on Selected Vegetables/Sun’s Soup.

   One randomized clinical trial (NCT00246727) of patients with stage IIIB or stage IV non-small cell lung cancer was conducted. The trial compared the survival of patients receiving Selected Vegetables/Sun’s Soup with patients receiving a placebo (inactive substance). Both groups received treatment with supportive care, such as radiation therapy, surgery, or palliative care.

7. Have any side effects or risks been reported from Selected Vegetables/Sun’s Soup?

   No harmful side effects or risks have been reported in the use of Selected Vegetables/Sun’s Soup. Some patients felt full or bloated after eating the dry form, but patients who ate the frozen mixture did not report this.

8. Is Selected Vegetables/Sun’s Soup approved by the U.S. Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The FDA has not approved any form of Selected Vegetables/Sun’s Soup for the treatment of cancer or any other medical condition. Well-designed clinical trials that test identical mixtures of vegetables and herbs are needed to prove whether Selected Vegetables/Sun’s Soup is useful in treating cancer.

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include:

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

1. What is PC-SPES?

   PC-SPES is a mixture of herbs that was sold as a complementary and alternative medicine (CAM) treatment for people with prostate cancer. The mixture contains these 8 herbs:

   • Baikal skullcap (Scutellaria baicalensis)
   • Chrysanthemum flowers (Dendranthema morifolium)
   • Reishi mushroom (Ganoderma lucidum)
   • Isatis (Isatis indigotica)
   • Licorice (Glycyrrhiza glabra or Glycyrrhiza uralensis)
   • Ginseng (Panax ginseng or Panax pseudoginseng var. notoginseng)
   • Rabdosia rubescens (Isodon rubescens)
   • Saw palmetto (Serenoa repens)

   PC-SPES was taken off the market because some batches were found to contain prescription medicines in addition to the herbs. Clinical trials of PC-SPES that were underway were stopped. There are products being sold now as substitutes for PC-SPES, but they are not the same mixture. Since the only company licensed to make PC-SPES is no longer in business, PC-SPES is not legally available in the United States.

2. What is the history of the discovery and use of PC-SPES as a complementary and alternative treatment for cancer?

   Most of the herbs in PC-SPES have been used in traditional Chinese medicine (TCM) for many health problems, including prostate problems, for hundreds of years. A chemist in New York and a doctor/herbalist in China worked together to create the mixture. In 1997, a company was formed to make PC-SPES and sell it in the United States without a prescription. Interest in PC-SPES grew, and researchers began looking at it. Tests found that some batches of PC-SPES contained one or more of the following drugs, which are not found in nature:

   • DES, a type of estrogen made in a lab.
   • Warfarin (Coumadin), a blood-thinner.
   • Indomethacin, a drug used to decrease inflammation.

   Because these drugs are to be used only by prescription and could be harmful to some people, PC-SPES was taken off the market in 2002.

3. What is the theory behind the claim that PC-SPES is useful in treating cancer?

   In lab tests, each herb used in PC-SPES has been reported to help keep cancer cells from growing or to help prevent cell damage that can lead to cancer and other diseases.

   PC-SPES was reported to slow the growth of prostate cancer but did not cure it. It is not known how PC-SPES works in the body. Some of the herbs in the mixture contain phytoestrogens, which are estrogen-like substances found in plants. Estrogen can cause the testicles to stop making testosterone, which makes some prostate cancers grow. Patients’ responses to PC-SPES were similar to responses to estrogen therapy using DES. The DES found in some batches of PC-SPES, however, may not have been enough to cause all of the estrogen-like effects that were seen in users of the mixture. There is some evidence that the mixture works in a different way than DES does, and that PC-SPES alone (without DES in it) may fight prostate cancer.

   PC-SPES has also shown anticancer effects on prostate cancers that do not depend on testosterone and on other types of cancer. This suggests that PC-SPES may have anticancer qualities other than its estrogen-like effects.

4. How is PC-SPES administered?

   PC-SPES is taken by mouth in capsules.

5. Have any preclinical (laboratory or animal) studies been conducted using PC-SPES?

   Studies of PC-SPES in test tubes and using rats showed that it might keep cancer cells from growing. These studies were done, however, before it became known that some batches of the product contained unlisted prescription medicines. Also, the product was not standardized (different batches of PC-SPES were found to contain different strengths of the herbal ingredients). For these reasons, the results of the lab tests and animal studies are not considered to be good evidence.

6. Have any clinical trials (research studies with people) of PC-SPES been conducted?

   Clinical trials of PC-SPES had begun before the product was taken off the market. In these trials, PC-SPES was reported to improve quality of life, reduce pain, and lower PSA (prostate specific antigen) levels in patients with prostate cancer. Rising PSA levels can be a sign that prostate cancer is growing.

   After it was learned that some batches of PC-SPES contained prescription medicines, ongoing studies were stopped and previous study results came into question. The responses reported in the studies may have been caused by the prescription medicines that were in the PC-SPES, as well as by the herbal ingredients. Also, since different batches of PC-SPES contained different ingredients, the studies cannot easily be compared.

7. Have any side effects or risks been reported from PC-SPES?

   Common side effects were the same as those reported with estrogen therapy:

   • Breast swelling and tenderness.
   • Loss of sex drive.
   • Impotence (inability to have an erection).

   There were other, less common, side effects:

   • Blood clots in the legs.
   • Diarrhea.

   PC-SPES may also change the way drugs, including anticancer drugs, work in the body. It may cause drugs to be more or less effective, or cause effects on the body that are not expected.

8. Is PC-SPES approved by the U.S. Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The U.S. Food and Drug Administration has not approved PC-SPES for use in cancer treatment. It is not legally sold in the United States.

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include:

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of Newcastle disease virus (NDV) as a treatment for people with cancer. The summary includes a brief history of NDV research, a review of laboratory and animal studies, the results of clinical trials, and possible side effects of NDV-based therapy. Several different strains of NDV will be discussed in the summary, including the Hungarian strain MTH (More Than Hope)-68. Information presented in some sections of the summary can also be found in tables located at the end of those sections.

This summary contains the following key information:

Many of the medical and scientific terms used in the summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

Information presented in this section about the use of Newcastle disease virus (NDV) in the treatment of human cancer is summarized in Table 1 below.

NDV is a paramyxovirus that causes Newcastle disease in a wide variety of birds (most notably, in chickens).[1–3] This often fatal disease is characterized by inflammation of respiratory tract and of either the brain or the gastrointestinal tract.[1,2,4,5] NDV can also infect humans, but, in humans, it is generally not very virulent, causing only mild flu-like symptoms or conjunctivitis and/or laryngitis.[1,6–14] The perception that NDV can replicate up to 10,000 times better in human cancer cells than in most normal human cells [2,6–10,12,13,15–23] has prompted much interest in this virus as a potential anticancer agent. This phenomenon is apparently caused by defects in intracellular antiviral defenses of some cancer cells.[24–26] NDV was historically considered a complementary and alternative medicine approach, but in recent years it has been extensively studied by the conventional medical community. Also, genetically engineered NDV strains are being developed and studied for their anticancer activity.[27]

The genetic material of NDV is RNA rather than DNA.[1,3,13,18,23,28–31] As with other types of viruses, essentially all of NDV’s replication cycle takes place inside infected cells, which are also known as host cells.[13,18,30,32] During a replication cycle, new virus proteins and copies of the NDV genetic material (i.e., genome) are made in the host cell’s cytoplasm. NDV is also an enveloped virus, which means that progeny virus particles are released from infected cells by budding off from them.[18,30,33] In this process, single copies of the NDV genome become wrapped in an outer coat (i.e., an envelope) that is made from a small piece of the host cell’s plasma membrane. Generally, the NDV outer coat contains only virus proteins that have been specifically inserted into the host cell’s plasma membrane;[18,28,32,33] however, some host cell proteins may be included as well.[34,35] Two specific virus proteins, hemagglutinin-neuraminidase and the fusion protein, are the main NDV proteins found in the outer coat of isolated virus particles.[3,18,28,30]

There are many different strains of NDV, and they have been classified as either lytic or nonlytic for human cells. Lytic strains and nonlytic strains both appear to replicate much more efficiently in human cancer cells than they do in most normal human cells,[12,13,15–20,36] and viruses of both strain types have been investigated as potential anticancer agents. One major difference between lytic strains and nonlytic strains is that lytic strains are able to make infectious progeny virus particles in human cells, whereas nonlytic strains are not.[13,18,28–30,37] This difference is due to the ability of lytic strains to produce activated hemagglutinin-neuraminidase and fusion protein molecules in the outer coat of progeny viruses in human cells. The progeny virus particles made by nonlytic strains contain inactive versions of these molecules. Activated hemagglutinin-neuraminidase and fusion protein molecules are required for NDV to enter a cell to replicate. Initial binding of NDV to a host cell takes place through the interaction of hemagglutinin-neuraminidase molecules in the virus coat with sialic-acid–containing molecules (i.e., gangliosides) on the surface of the cell. It is important to note, however, that nonlytic strains of NDV can make infectious progeny viruses in some types of nonhuman cells (e.g., chicken embryo cells), thereby allowing these strains to be maintained.[13,18,28,29,36]

Another major difference between lytic strains and nonlytic strains is that, although they both have the potential to kill infected cells, the mechanisms by which they accomplish this result are different. The production of infectious progeny virus particles by lytic strains gives them the ability to kill host cells fairly quickly. The budding of progeny viruses that contain activated hemagglutinin-neuraminidase and fusion protein molecules in their outer coats causes the plasma membrane of NDV-infected cells to fuse with the plasma membrane of adjacent cells, leading to the production of large, inviable fused cells known as syncytia.[12,13,18,30] The more efficiently a lytic strain can replicate inside a host cell, the more quickly it can kill that cell. The preferential killing of cancer cells by a lytic virus is known as oncolysis; thus, lytic strains of NDV are also called oncolytic strains. Nonlytic strains of NDV kill infected cells more slowly, with death apparently the result of viral disruption of normal host cell metabolism.[36,38]

The specific mechanism by which nonlytic NDV strains cause cell death in cancer cells has not been completely elucidated, but in Vero cells (derived from kidney epithelium) it was determined that NDV caused cell death by decreasing DNA content, increasing the ratio of Bax to Bcl-2, increasing p53 level, and increasing caspase expression, resulting in apoptosis.[39–41]

As indicated previously, both lytic strains and nonlytic strains have been investigated for their anticancer potential. In fact, the major differences between the two strain types have been exploited to develop three different approaches to cancer therapy:

One proposed advantage of the first approach is that virus replication may allow the spread of cytotoxic viruses to every cancer cell in the body;[8,34] however, the production of virus-neutralizing antibodies by the immune system might limit this possibility.[6,8,13,30,40] The rationale for the second and third approaches is that tumor-specific antigens (i.e., proteins or other molecules that are generally located in the plasma membrane of cancer cells and that are either unique to cancer cells or much more abundant in them) may be better recognized by the immune system if they are associated with virus antigens (i.e., virus proteins that have been inserted into the plasma membrane of host cells).[8,12,13,28,32,34,42–48] If this enhanced recognition takes place, then it may increase the chance that cancer cells, whether they are virus infected or not, will be recognized as foreign by the immune system and be destroyed.[8,12,28,47,48]

The principal developers of the third approach have stated that whole cell vaccines can stimulate the immune system better than oncolysates, and that cells infected with a nonlytic strain of NDV will remain intact in the body long enough to generate these more effective immune responses.[18,28,29,36–38,43,46,49–51] It should be noted that the cancer cells used in the third approach are treated with enough gamma radiation to prevent further cell division, but not enough to cause cell death, either before or after they are infected with the nonlytic virus.[49,50,52–58,13] This precaution ensures that patients are not given a vaccine that contains actively proliferating cancer cells.

Either a patient’s own cancer cells (i.e., autologous cells) or cells from another patient with the same type of cancer (i.e., allogeneic cells) can be used to make oncolysates and whole cell vaccines. It is important to note that immune system responses similar to those obtained with oncolysates and whole cell vaccines may occur in patients infected with a lytic strain of NDV and that these responses would be expected to contribute to any observed anticancer effect.

To conduct human studies with viruses, vaccines, or other biological materials in the United States, researchers must file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). Biological materials and drugs have been held to similar safety and effectiveness standards since 1972. In an IND application, researchers must provide safety and toxicity data from laboratory and animal studies to justify the dose, the route, and the schedule of administration to be used in the proposed clinical studies. Among the safety issues to be addressed, researchers must demonstrate an absence of harmful contaminants. Most human studies of NDV as an anticancer agent have taken place outside the United States; therefore, they have not required an IND. At present, at least one group of U.S. investigators has filed an IND application to study NDV as an anticancer treatment.[59] It should be noted that the FDA has not approved the use of NDV to treat any medical condition.

The NDV strains that have been evaluated most widely for the treatment of cancer are 73-T, MTH-68, and Ulster.[1,6,11,22,42,45,49–58,60–74] Strain 73-T is lytic, and Ulster is nonlytic. Strain MTH-68 has not been classified, but it is assumed to be lytic.[1,6,66,75,22,76,77] All three strains have shown little or no evidence of neurotropism (i.e., an ability to replicate efficiently in normal nerve cells or normal neural tissue).

In animal studies, NDV infection has been accomplished by intratumoral, intraperitoneal, intravenous, intramuscular, or subcutaneous injection.[9,10,12,23,28,36,36,43,78] NDV-infected, whole cell vaccines have been given to animals by intraperitoneal,[46] intradermal,[47] or subcutaneous injection,or by a combination of subcutaneous and intramuscular injection.[36,43,79]

In human studies, NDV oncolysates have been administered by subcutaneous [11,42,45,60,63,65,67–70] or intradermal [62,64] injection. NDV-infected, whole cell vaccines have been administered by intradermal injection only.[49,50,52–58,71–73] In cases where patients have been infected with a lytic strain of NDV, intratumoral,[20] intravenous,[1,59,66,80] or intramuscular [61] injection has been used, as have inhalation [1,6] and direct injection into the colon (i.e., via a colostomy opening).[1] In some instances, cytokine treatment has been combined with NDV therapy.[45,52,53,56,62,64,65,70]

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36. Schirrmacher V, Griesbach A, Ahlert T: Antitumor effects of Newcastle Disease Virus in vivo: local versus systemic effects. Int J Oncol 18 (5): 945-52, 2001. [PUBMED Abstract]
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39. Ravindra PV, Tiwari AK, Ratta B, et al.: Newcastle disease virus-induced cytopathic effect in infected cells is caused by apoptosis. Virus Res 141 (1): 13-20, 2009. [PUBMED Abstract]
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42. Cassel WA, Murray DR: A ten-year follow-up on stage II malignant melanoma patients treated postsurgically with Newcastle disease virus oncolysate. Med Oncol Tumor Pharmacother 9 (4): 169-71, 1992. [PUBMED Abstract]
43. Heicappell R, Schirrmacher V, von Hoegen P, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects. Int J Cancer 37 (4): 569-77, 1986. [PUBMED Abstract]
44. Shoham J, Hirsch R, Zakay-Rones Z, et al.: Augmentation of tumor cell immunogenicity by viruses–an approach to specific immunotherapy of cancer. Nat Immun Cell Growth Regul 9 (3): 165-72, 1990. [PUBMED Abstract]
45. Zorn U, Duensing S, Langkopf F, et al.: Active specific immunotherapy of renal cell carcinoma: cellular and humoral immune responses. Cancer Biother Radiopharm 12 (3): 157-65, 1997. [PUBMED Abstract]
46. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994. [PUBMED Abstract]
47. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989. [PUBMED Abstract]
48. DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Lippincott-Raven Publishers, 1997.
49. Liebrich W, Schlag P, Manasterski M, et al.: In vitro and clinical characterisation of a Newcastle disease virus-modified autologous tumour cell vaccine for treatment of colorectal cancer patients. Eur J Cancer 27 (6): 703-10, 1991. [PUBMED Abstract]
50. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996. [PUBMED Abstract]
51. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient’s own immune system. Onkologie 16 (5): 290-6, 1993.
52. Ahlert T, Sauerbrei W, Bastert G, et al.: Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer. J Clin Oncol 15 (4): 1354-66, 1997. [PUBMED Abstract]
53. Ahlert T: Tumor cell vaccination and IL-2 therapy. Hybridoma 12 (5): 549-52, 1993. [PUBMED Abstract]
54. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990. [PUBMED Abstract]
55. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990. [PUBMED Abstract]
56. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN-alpha(2b). Int J Oncol 6 (5): 947-54, 1995. [PUBMED Abstract]
57. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992. [PUBMED Abstract]
58. Möbus V, Horn S, Stöck M, et al.: Tumor cell vaccination for gynecological tumors. Hybridoma 12 (5): 543-7, 1993. [PUBMED Abstract]
59. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002. [PUBMED Abstract]
60. Cassel WA, Murray DR, Phillips HS: A phase II study on the postsurgical management of Stage II malignant melanoma with a Newcastle disease virus oncolysate. Cancer 52 (5): 856-60, 1983. [PUBMED Abstract]
61. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971. [PUBMED Abstract]
62. Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993. [PUBMED Abstract]
63. Plager C, Bowen JM, Fenoglio C, et al.: Adjuvant immunotherapy of M.D. Anderson Hospital (MDAH) stage III-B malignant melanoma with Newcastle disease virus oncolysate. [Abstract] Proceedings of the American Society of Clinical Oncology 9: A-1091, 281, 1990.
64. Mallmann P, Eis-Hubinger AM, Krebs D: Lymphokine-activated tumor-infiltrating lymphocytes and autologous tumor vaccine in breast and ovarian cancer. Onkologie 15 (6): 490-6, 1992.
65. Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996. [PUBMED Abstract]
66. Csatary LK, Bakács T: Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 281 (17): 1588-9, 1999. [PUBMED Abstract]
67. Cassel WA, Murras DR, Torbin AH, et al.: Viral oncolysate in the management of malignant melanoma. I. Preparation of the oncolysate and measurement of immunologic responses. Cancer 40 (2): 672-9, 1977. [PUBMED Abstract]
68. Murray DR, Cassel WA, Torbin AH, et al.: Viral oncolysate in the management of malignant melanoma. II. Clinical studies. Cancer 40 (2): 680-6, 1977. [PUBMED Abstract]
69. Cassel WA, Murray DR: Treatment of stage II malignant melanoma patients with a Newcastle disease virus oncolysate. Nat Immun Cell Growth Regul 7 (5-6): 351-2, 1988. [PUBMED Abstract]
70. Kirchner HH, Anton P, Atzpodien J: Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 13 (3): 171-3, 1995. [PUBMED Abstract]
71. Proebstle TM, Staib G, Kaufmann R, et al.: Autologous active specific immunization (ASI) therapy for metastatic melanoma [abstract from Fifth World Conference on Cancers of the Skin]. [Abstract] Melanoma Res 3: A-133, 35, 1993.
72. Schirrmacher V: [Anti-tumor vaccination] Zentralbl Chir 125 (Suppl 1): 33-6, 2000. [PUBMED Abstract]
73. Pomer S, Thiele R, Staehler G, et al.: [Tumor vaccination in renal cell carcinoma with and without interleukin-2 (IL-2) as adjuvant. A clinical contribution to the development of effective active specific immunization] Urologe A 34 (3): 215-20, 1995. [PUBMED Abstract]
74. Schirrmacher V, Schlag P, Liebrich W, et al.: Specific immunotherapy of colorectal carcinoma with Newcastle-disease virus-modified autologous tumor cells prepared from resected liver metastasis. Ann N Y Acad Sci 690: 364-6, 1993. [PUBMED Abstract]
75. Fábián Z, Csatary CM, Szeberényi J, et al.: p53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines. J Virol 81 (6): 2817-30, 2007. [PUBMED Abstract]
76. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993. [PUBMED Abstract]
77. Fábián Z, Töröcsik B, Kiss K, et al.: Induction of apoptosis by a Newcastle disease virus vaccine (MTH-68/H) in PC12 rat phaeochromocytoma cells. Anticancer Res 21 (1A): 125-35, 2001 Jan-Feb. [PUBMED Abstract]
78. Schirrmacher V, Bai L, Umansky V, et al.: Newcastle disease virus activates macrophages for anti-tumor activity. Int J Oncol 16 (2): 363-73, 2000. [PUBMED Abstract]
79. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun. [PUBMED Abstract]
80. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964.
81. Freeman AI, Zakay-Rones Z, Gomori JM, et al.: Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 13 (1): 221-8, 2006. [PUBMED Abstract]
82. Liang W, Wang H, Sun TM, et al.: Application of autologous tumor cell vaccine and NDV vaccine in treatment of tumors of digestive tract. World J Gastroenterol 9 (3): 495-8, 2003. [PUBMED Abstract]

The first published report to establish a link between infection with a virus and the regression of cancer appeared in 1912.[1–6] This report described a woman whose cervical cancer improved following treatment to prevent rabies. The woman had been bitten by a dog, and she was subsequently injected with a vaccine made of attenuated (i.e., weakened) rabies virus. Over the next 60 years, many other viruses, including Newcastle disease virus (NDV), were shown to have anticancer potential.[1,3–25] The first report of positive results using NDV as a treatment for human cancer was published in 1964.[9] By that time, attenuated strains of NDV had been used for almost 2 decades to prevent Newcastle disease in birds, and the inability of this virus to cause serious illness in humans had been established.

As indicated previously (refer to the General Information section of this summary for more information), cells infected with NDV can be killed directly by the virus or indirectly through an immune system response to the infection. The immune system uses a variety of approaches to kill virus-infected cells, including attack by cytotoxic cells (i.e., natural killer cells and/or cytotoxic T cells); attack by antivirus antibodies, which are made by B cells; and the release of cytokines.[2,6,15,18,22,25–28]

Cytokines can be directly cytotoxic to virus-infected cells (e.g., tumor necrosis factor [TNF]-alpha).[14,15,20] In addition, they can stimulate increases in the activity and/or numbers of specific types of immune system cells (e.g., interferon-alpha, interferon-gamma, and TNF-alpha).[2,29–31]

As also indicated previously (refer to the General Information section of this summary for more information), if the immune system is responding to virus-infected cancer cells (or fragments of cancer cells), then better recognition of tumor-specific antigens may occur, and an increased ability to kill uninfected cancer cells may be acquired.[15,18,19,23,26,30,32–38] The immune system would use the same approaches to kill uninfected cancer cells that it uses to kill virus-infected cells. For example, it has been shown that TNF-alpha is directly cytotoxic to some, but not all, cancer cells, whereas normal cells are not harmed by this cytokine.[39–42]

References

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2. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993. [PUBMED Abstract]
3. Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999.
4. Webb HE, Smith CE: Viruses in the treatment of cancer. Lancet 1 (7658): 1206-8, 1970. [PUBMED Abstract]
5. Ahlert T, Schirrmacher V: Isolation of a human melanoma adapted Newcastle disease virus mutant with highly selective replication patterns. Cancer Res 50 (18): 5962-8, 1990. [PUBMED Abstract]
6. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993. [PUBMED Abstract]
7. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18 (7): 863-8, 1965.
8. Eaton MD, Heller JA, Scala AR: Enhancement of lymphoma cell immunogenicity by infection with nononcogenic virus. Cancer Res 33 (12): 3293-8, 1973. [PUBMED Abstract]
9. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964.
10. Flanagan AD, Love R, Tesar W: Propagation of Newcastle disease virus in Ehrlich ascites cells in vitro and in vivo. Proc Soc Exp Biol Med 90 (1): 82-6, 1955. [PUBMED Abstract]
11. Sinkovics JG, Howe CD: Superinfection of tumors with viruses. Experientia 25 (7): 733-4, 1969. [PUBMED Abstract]
12. Eaton MD, Levinthal JD, Scala AR: Contribution of antiviral immunity to oncolysis by Newcastle disease virus in a murine lymphoma. J Natl Cancer Inst 39 (6): 1089-97, 1967. [PUBMED Abstract]
13. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb. [PUBMED Abstract]
14. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for “therapeutic” viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994. [PUBMED Abstract]
15. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996. [PUBMED Abstract]
16. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994. [PUBMED Abstract]
17. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994. [PUBMED Abstract]
18. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992. [PUBMED Abstract]
19. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998. [PUBMED Abstract]
20. Lorence RM, Rood PA, Kelley KW: Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. J Natl Cancer Inst 80 (16): 1305-12, 1988. [PUBMED Abstract]
21. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999. [PUBMED Abstract]
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23. Shoham J, Hirsch R, Zakay-Rones Z, et al.: Augmentation of tumor cell immunogenicity by viruses–an approach to specific immunotherapy of cancer. Nat Immun Cell Growth Regul 9 (3): 165-72, 1990. [PUBMED Abstract]
24. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971. [PUBMED Abstract]
25. Bridgewater J, Collins M: Vaccine immunotherapy for cancer. Mol Cell Biol Hum Dis Ser 5: 140-56, 1995. [PUBMED Abstract]
26. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
27. Cooper NR, Nemerow GR: The role of antibody and complement in the control of viral infections. J Invest Dermatol 83 (1 Suppl): 121s-127s, 1984. [PUBMED Abstract]
28. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. Garland Publishing, 1994.
29. Zorn U, Dallmann I, Grosse J, et al.: Induction of cytokines and cytotoxicity against tumor cells by Newcastle disease virus. Cancer Biother 9 (3): 225-35, 1994 Fall. [PUBMED Abstract]
30. DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Lippincott-Raven Publishers, 1997.
31. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990. [PUBMED Abstract]
32. Haas C, Ertel C, Gerhards R, et al.: Introduction of adhesive and costimulatory immune functions into tumor cells by infection with Newcastle Disease Virus. Int J Oncol 13 (6): 1105-15, 1998. [PUBMED Abstract]
33. Cassel WA, Murray DR: A ten-year follow-up on stage II malignant melanoma patients treated postsurgically with Newcastle disease virus oncolysate. Med Oncol Tumor Pharmacother 9 (4): 169-71, 1992. [PUBMED Abstract]
34. Heicappell R, Schirrmacher V, von Hoegen P, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects. Int J Cancer 37 (4): 569-77, 1986. [PUBMED Abstract]
35. Zorn U, Duensing S, Langkopf F, et al.: Active specific immunotherapy of renal cell carcinoma: cellular and humoral immune responses. Cancer Biother Radiopharm 12 (3): 157-65, 1997. [PUBMED Abstract]
36. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994. [PUBMED Abstract]
37. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989. [PUBMED Abstract]
38. Nesselhut T: Influence on antigen exposition of tumor cells by membrane active substances and viral infections. Hybridoma 12 (5): 553-7, 1993. [PUBMED Abstract]
39. Helson L, Green S, Carswell E, et al.: Effect of tumour necrosis factor on cultured human melanoma cells. Nature 258 (5537): 731-2, 1975. [PUBMED Abstract]
40. Haranaka K, Satomi N: Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro. Jpn J Exp Med 51 (3): 191-4, 1981. [PUBMED Abstract]
41. Sugarman BJ, Aggarwal BB, Hass PE, et al.: Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 230 (4728): 943-5, 1985. [PUBMED Abstract]
42. Fransen L, Van der Heyden J, Ruysschaert R, et al.: Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol 22 (4): 419-26, 1986. [PUBMED Abstract]

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1. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994. [PUBMED Abstract]
2. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994. [PUBMED Abstract]
3. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992. [PUBMED Abstract]
4. Bar-Eli N, Giloh H, Schlesinger M, et al.: Preferential cytotoxic effect of Newcastle disease virus on lymphoma cells. J Cancer Res Clin Oncol 122 (7): 409-15, 1996. [PUBMED Abstract]
5. Tzadok-David Y, Metzkin-Eizenberg M, Zakay-Rones Z: The effect of a mesogenic and a lentogenic Newcastle disease virus strain on Burkitt lymphoma Daudi cells. J Cancer Res Clin Oncol 121 (3): 169-74, 1995. [PUBMED Abstract]
6. Lorence RM, Rood PA, Kelley KW: Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. J Natl Cancer Inst 80 (16): 1305-12, 1988. [PUBMED Abstract]
7. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999. [PUBMED Abstract]
8. Zorn U, Dallmann I, Grosse J, et al.: Induction of cytokines and cytotoxicity against tumor cells by Newcastle disease virus. Cancer Biother 9 (3): 225-35, 1994 Fall. [PUBMED Abstract]
9. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18 (7): 863-8, 1965.
10. Phuangsab A, Lorence RM, Reichard KW, et al.: Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett 172 (1): 27-36, 2001. [PUBMED Abstract]
11. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
12. Ahlert T, Schirrmacher V: Isolation of a human melanoma adapted Newcastle disease virus mutant with highly selective replication patterns. Cancer Res 50 (18): 5962-8, 1990. [PUBMED Abstract]
13. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996. [PUBMED Abstract]
14. Schirrmacher V, Griesbach A, Ahlert T: Antitumor effects of Newcastle Disease Virus in vivo: local versus systemic effects. Int J Oncol 18 (5): 945-52, 2001. [PUBMED Abstract]
15. Puhlmann J, Puehler F, Mumberg D, et al.: Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus. Oncogene 29 (15): 2205-16, 2010. [PUBMED Abstract]
16. Russell SJ: RNA viruses as virotherapy agents. Cancer Gene Ther 9 (12): 961-6, 2002. [PUBMED Abstract]
17. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb. [PUBMED Abstract]
18. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993. [PUBMED Abstract]
19. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for “therapeutic” viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994. [PUBMED Abstract]
20. Batliwalla FM, Bateman BA, Serrano D, et al.: A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4 (12): 783-94, 1998. [PUBMED Abstract]
21. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998. [PUBMED Abstract]
22. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996.
23. Zulkifli MM, Ibrahim R, Ali AM, et al.: Newcastle diseases virus strain V4UPM displayed oncolytic ability against experimental human malignant glioma. Neurol Res 31 (1): 3-10, 2009. [PUBMED Abstract]
24. Schneider T, Gerhards R, Kirches E, et al.: Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neurooncol 53 (1): 39-46, 2001. [PUBMED Abstract]
25. Sinkovics JG, Horvath JC: Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 16 (1): 1-15, 2000. [PUBMED Abstract]
26. Schirrmacher V, Jurianz K, Roth C, et al.: Tumor stimulator cell modification by infection with Newcastle Disease Virus: analysis of effects and mechanism in MLTC-CML cultures. Int J Oncol 14 (2): 205-15, 1999. [PUBMED Abstract]
27. Kadish AS, Doyle AT, Steinhauer EH, et al.: Natural cytotoxicity and interferon production in human cancer: deficient natural killer activity and normal interferon production in patients with advanced disease. J Immunol 127 (5): 1817-22, 1981. [PUBMED Abstract]
28. Budzynski W, Radzikowski C: Cytotoxic cells in immunodeficient athymic mice. Immunopharmacol Immunotoxicol 16 (3): 319-46, 1994. [PUBMED Abstract]
29. Schirrmacher V, Haas C, Bonifer R, et al.: Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 3 (7): 1135-48, 1997. [PUBMED Abstract]
30. Haas C, Herold-Mende C, Gerhards R, et al.: An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules. Cancer Gene Ther 6 (3): 254-62, 1999 May-Jun. [PUBMED Abstract]
31. Haas C, Ertel C, Gerhards R, et al.: Introduction of adhesive and costimulatory immune functions into tumor cells by infection with Newcastle Disease Virus. Int J Oncol 13 (6): 1105-15, 1998. [PUBMED Abstract]
32. Heicappell R, Schirrmacher V, von Hoegen P, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects. Int J Cancer 37 (4): 569-77, 1986. [PUBMED Abstract]
33. Shoham J, Hirsch R, Zakay-Rones Z, et al.: Augmentation of tumor cell immunogenicity by viruses–an approach to specific immunotherapy of cancer. Nat Immun Cell Growth Regul 9 (3): 165-72, 1990. [PUBMED Abstract]
34. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994. [PUBMED Abstract]
35. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989. [PUBMED Abstract]
36. Schirrmacher V, Bai L, Umansky V, et al.: Newcastle disease virus activates macrophages for anti-tumor activity. Int J Oncol 16 (2): 363-73, 2000. [PUBMED Abstract]
37. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun. [PUBMED Abstract]
38. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990. [PUBMED Abstract]
39. Haas C, Strauss G, Moldenhauer G, et al.: Bispecific antibodies increase T-cell stimulatory capacity in vitro of human autologous virus-modified tumor vaccine. Clin Cancer Res 4 (3): 721-30, 1998. [PUBMED Abstract]
40. Von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18 (8): 1159-66, 1988. [PUBMED Abstract]
41. Schirrmacher V, Schild HJ, Gückel B, et al.: Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. Immunol Cell Biol 71 ( Pt 4): 311-26, 1993. [PUBMED Abstract]
42. Bai L, Koopmann J, Fiola C, et al.: Dendritic cells pulsed with viral oncolysates potently stimulate autologous T cells from cancer patients. Int J Oncol 21 (4): 685-94, 2002. [PUBMED Abstract]
43. Washburn B, Schirrmacher V: Human tumor cell infection by Newcastle Disease Virus leads to upregulation of HLA and cell adhesion molecules and to induction of interferons, chemokines and finally apoptosis. Int J Oncol 21 (1): 85-93, 2002. [PUBMED Abstract]
44. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient’s own immune system. Onkologie 16 (5): 290-6, 1993.
45. Haas C, Schirrmacher V: Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies. Cancer Immunol Immunother 43 (3): 190-4, 1996. [PUBMED Abstract]
46. Schirrmacher V, von Hoegen P, Heicappell R: Virus modified tumor cell vaccines for active specific immunotherapy of micrometastases: expansion and activation of tumor-specific T cells. Prog Clin Biol Res 288: 391-9, 1989. [PUBMED Abstract]
47. Schirrmacher V, von Hoegen P, Heicappell R: Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. Adv Exp Med Biol 233: 91-6, 1988. [PUBMED Abstract]
48. Schirrmacher V, Haas C: Modification of cancer vaccines by virus infection and attachment of bispecific antibodies. In: Walden P, Trefzer U, Sterry W, et al., eds.: Gene Therapy of Cancer. Plenum Press, 1998, pp 251-7.
49. Termeer CC, Schirrmacher V, Bröcker EB, et al.: Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells. Cancer Gene Ther 7 (2): 316-23, 2000. [PUBMED Abstract]
50. Haas C, Lulei M, Fournier P, et al.: A tumor vaccine containing anti-CD3 and anti-CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes. Int J Cancer 118 (3): 658-67, 2006. [PUBMED Abstract]
51. Haas C, Lulei M, Fournier P, et al.: T-cell triggering by CD3- and CD28-binding molecules linked to a human virus-modified tumor cell vaccine. Vaccine 23 (19): 2439-53, 2005. [PUBMED Abstract]
52. Washburn B, Weigand MA, Grosse-Wilde A, et al.: TNF-related apoptosis-inducing ligand mediates tumoricidal activity of human monocytes stimulated by Newcastle disease virus. J Immunol 170 (4): 1814-21, 2003. [PUBMED Abstract]

The anticancer potential of Newcastle disease virus (NDV) has been investigated in clinical studies in the United States, Canada, China, Germany, and Hungary. These studies have evaluated the use of oncolysates,[1–14] whole cell vaccines,[14–37] and infection of patients with a lytic strain of the virus.[14,38–52] Findings from most of the studies, almost all of which were phase I or phase II clinical trials, have been reported in English-language biomedical journals. Overall, the results of these studies must be considered preliminary. Most studies enrolled only small numbers of patients, and historical control subjects, rather than actual control groups, which were often used for outcome comparisons. In addition, the evaluation of many studies is made difficult by poor descriptions of study design and the incomplete reporting of clinical data.

References

1. Batliwalla FM, Bateman BA, Serrano D, et al.: A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4 (12): 783-94, 1998. [PUBMED Abstract]
2. Cassel WA, Murray DR: A ten-year follow-up on stage II malignant melanoma patients treated postsurgically with Newcastle disease virus oncolysate. Med Oncol Tumor Pharmacother 9 (4): 169-71, 1992. [PUBMED Abstract]
3. Zorn U, Duensing S, Langkopf F, et al.: Active specific immunotherapy of renal cell carcinoma: cellular and humoral immune responses. Cancer Biother Radiopharm 12 (3): 157-65, 1997. [PUBMED Abstract]
4. Cassel WA, Murray DR, Phillips HS: A phase II study on the postsurgical management of Stage II malignant melanoma with a Newcastle disease virus oncolysate. Cancer 52 (5): 856-60, 1983. [PUBMED Abstract]
5. Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993. [PUBMED Abstract]
6. Plager C, Bowen JM, Fenoglio C, et al.: Adjuvant immunotherapy of M.D. Anderson Hospital (MDAH) stage III-B malignant melanoma with Newcastle disease virus oncolysate. [Abstract] Proceedings of the American Society of Clinical Oncology 9: A-1091, 281, 1990.
7. Mallmann P, Eis-Hubinger AM, Krebs D: Lymphokine-activated tumor-infiltrating lymphocytes and autologous tumor vaccine in breast and ovarian cancer. Onkologie 15 (6): 490-6, 1992.
8. Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996. [PUBMED Abstract]
9. Cassel WA, Murras DR, Torbin AH, et al.: Viral oncolysate in the management of malignant melanoma. I. Preparation of the oncolysate and measurement of immunologic responses. Cancer 40 (2): 672-9, 1977. [PUBMED Abstract]
10. Murray DR, Cassel WA, Torbin AH, et al.: Viral oncolysate in the management of malignant melanoma. II. Clinical studies. Cancer 40 (2): 680-6, 1977. [PUBMED Abstract]
11. Cassel WA, Murray DR: Treatment of stage II malignant melanoma patients with a Newcastle disease virus oncolysate. Nat Immun Cell Growth Regul 7 (5-6): 351-2, 1988. [PUBMED Abstract]
12. Kirchner HH, Anton P, Atzpodien J: Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 13 (3): 171-3, 1995. [PUBMED Abstract]
13. Savage HE, Rossen RD, Hersh EM, et al.: Antibody development to viral and allogeneic tumor cell-associated antigens in patients with malignant melanoma and ovarian carcinoma treated with lysates of virus-infected tumor cells. Cancer Res 46 (4 Pt 2): 2127-33, 1986. [PUBMED Abstract]
14. Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999.
15. Liebrich W, Schlag P, Manasterski M, et al.: In vitro and clinical characterisation of a Newcastle disease virus-modified autologous tumour cell vaccine for treatment of colorectal cancer patients. Eur J Cancer 27 (6): 703-10, 1991. [PUBMED Abstract]
16. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996. [PUBMED Abstract]
17. Ahlert T, Sauerbrei W, Bastert G, et al.: Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer. J Clin Oncol 15 (4): 1354-66, 1997. [PUBMED Abstract]
18. Ahlert T: Tumor cell vaccination and IL-2 therapy. Hybridoma 12 (5): 549-52, 1993. [PUBMED Abstract]
19. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990. [PUBMED Abstract]
20. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990. [PUBMED Abstract]
21. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN-alpha(2b). Int J Oncol 6 (5): 947-54, 1995. [PUBMED Abstract]
22. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992. [PUBMED Abstract]
23. Möbus V, Horn S, Stöck M, et al.: Tumor cell vaccination for gynecological tumors. Hybridoma 12 (5): 543-7, 1993. [PUBMED Abstract]
24. Proebstle TM, Staib G, Kaufmann R, et al.: Autologous active specific immunization (ASI) therapy for metastatic melanoma [abstract from Fifth World Conference on Cancers of the Skin]. [Abstract] Melanoma Res 3: A-133, 35, 1993.
25. Schirrmacher V: [Anti-tumor vaccination] Zentralbl Chir 125 (Suppl 1): 33-6, 2000. [PUBMED Abstract]
26. Pomer S, Thiele R, Staehler G, et al.: [Tumor vaccination in renal cell carcinoma with and without interleukin-2 (IL-2) as adjuvant. A clinical contribution to the development of effective active specific immunization] Urologe A 34 (3): 215-20, 1995. [PUBMED Abstract]
27. Stoeck M, Marland-Noske C, Manasterski M, et al.: In vitro expansion and analysis of T lymphocyte microcultures obtained from the vaccination sites of cancer patients undergoing active specific immunization with autologous Newcastle-disease-virus-modified tumour cells. Cancer Immunol Immunother 37 (4): 240-4, 1993. [PUBMED Abstract]
28. Herold-Mende C, Karcher J, Dyckhoff G, et al.: Antitumor immunization of head and neck squamous cell carcinoma patients with a virus-modified autologous tumor cell vaccine. Adv Otorhinolaryngol 62: 173-83, 2005. [PUBMED Abstract]
29. Schulze T, Kemmner W, Weitz J, et al.: Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother 58 (1): 61-9, 2009. [PUBMED Abstract]
30. Schneider T, Gerhards R, Kirches E, et al.: Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neurooncol 53 (1): 39-46, 2001. [PUBMED Abstract]
31. Steiner HH, Bonsanto MM, Beckhove P, et al.: Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 22 (21): 4272-81, 2004. [PUBMED Abstract]
32. Voit C, Kron M, Schwürzer-Voit M, et al.: Intradermal injection of Newcastle disease virus-modified autologous melanoma cell lysate and interleukin-2 for adjuvant treatment of melanoma patients with resectable stage III disease. J Dtsch Dermatol Ges 1 (2): 120-5, 2003. [PUBMED Abstract]
33. Liang W, Wang H, Sun TM, et al.: Application of autologous tumor cell vaccine and NDV vaccine in treatment of tumors of digestive tract. World J Gastroenterol 9 (3): 495-8, 2003. [PUBMED Abstract]
34. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998. [PUBMED Abstract]
35. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient’s own immune system. Onkologie 16 (5): 290-6, 1993.
36. Schirrmacher V, Schlag P, Liebrich W, et al.: Specific immunotherapy of colorectal carcinoma with Newcastle-disease virus-modified autologous tumor cells prepared from resected liver metastasis. Ann N Y Acad Sci 690: 364-6, 1993. [PUBMED Abstract]
37. Schirrmacher V: Clinical trials of antitumor vaccination with an autologous tumor cell vaccine modified by virus infection: improvement of patient survival based on improved antitumor immune memory. Cancer Immunol Immunother 54 (6): 587-98, 2005. [PUBMED Abstract]
38. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb. [PUBMED Abstract]
39. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993. [PUBMED Abstract]
40. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18 (7): 863-8, 1965.
41. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971. [PUBMED Abstract]
42. Csatary LK, Bakács T: Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 281 (17): 1588-9, 1999. [PUBMED Abstract]
43. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964.
44. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002. [PUBMED Abstract]
45. Laurie SA, Bell JC, Atkins HL, et al.: A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization. Clin Cancer Res 12 (8): 2555-62, 2006. [PUBMED Abstract]
46. Freeman AI, Zakay-Rones Z, Gomori JM, et al.: Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 13 (1): 221-8, 2006. [PUBMED Abstract]
47. Csatary LK, Gosztonyi G, Szeberenyi J, et al.: MTH-68/H oncolytic viral treatment in human high-grade gliomas. J Neurooncol 67 (1-2): 83-93, 2004 Mar-Apr. [PUBMED Abstract]
48. Wagner S, Csatary CM, Gosztonyi G, et al.: Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid. APMIS 114 (10): 731-43, 2006. [PUBMED Abstract]
49. Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91 (20): 1708-10, 1999. [PUBMED Abstract]
50. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996.
51. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993. [PUBMED Abstract]
52. Lorence RM, Roberts MS, O’Neil JD, et al.: Phase 1 clinical experience using intravenous administration of PV701, an oncolytic Newcastle disease virus. Curr Cancer Drug Targets 7 (2): 157-67, 2007. [PUBMED Abstract]
53. Karcher J, Dyckhoff G, Beckhove P, et al.: Antitumor vaccination in patients with head and neck squamous cell carcinomas with autologous virus-modified tumor cells. Cancer Res 64 (21): 8057-61, 2004. [PUBMED Abstract]
54. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994. [PUBMED Abstract]
55. Von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18 (8): 1159-66, 1988. [PUBMED Abstract]
56. Schirrmacher V, Schild HJ, Gückel B, et al.: Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. Immunol Cell Biol 71 ( Pt 4): 311-26, 1993. [PUBMED Abstract]
57. Bosslet K, Schirrmacher V, Shantz G: Tumor metastases and cell-mediated immunity in a model system in DBA/2 mice. VI. Similar specificity patterns of protective anti-tumor immunity in vivo and of cytolytic T cells in vitro. Int J Cancer 24 (3): 303-13, 1979. [PUBMED Abstract]
58. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999. [PUBMED Abstract]
59. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
60. Schirrmacher V, Haas C, Bonifer R, et al.: Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 3 (7): 1135-48, 1997. [PUBMED Abstract]
61. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989. [PUBMED Abstract]
62. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun. [PUBMED Abstract]
63. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990. [PUBMED Abstract]
64. Schirrmacher V, von Hoegen P, Heicappell R: Virus modified tumor cell vaccines for active specific immunotherapy of micrometastases: expansion and activation of tumor-specific T cells. Prog Clin Biol Res 288: 391-9, 1989. [PUBMED Abstract]
65. Schirrmacher V, von Hoegen P, Heicappell R: Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. Adv Exp Med Biol 233: 91-6, 1988. [PUBMED Abstract]
66. von Hoegen P, Heicappell R, Griesbach A, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. III. Postoperative activation of tumor-specific CTLP from mice with metastases requires stimulation with the specific antigen plus additional signals. Invasion Metastasis 9 (2): 117-33, 1989. [PUBMED Abstract]
67. Patel BT, Lutz MB, Schlag P, et al.: An analysis of autologous T-cell anti-tumour responses in colon-carcinoma patients following active specific immunization (ASI). Int J Cancer 51 (6): 878-85, 1992. [PUBMED Abstract]
68. Ilan Y, Sauter B, Chowdhury NR, et al.: Oral tolerization to adenoviral proteins permits repeated adenovirus-mediated gene therapy in rats with pre-existing immunity to adenoviruses. Hepatology 27 (5): 1368-76, 1998. [PUBMED Abstract]
69. Ilan Y, Chowdhury JR: Induction of tolerance to hepatitis B virus: can we ‘eat the disease’ and live with the virus? Med Hypotheses 52 (6): 505-9, 1999. [PUBMED Abstract]

The side effects associated with exposure to Newcastle disease virus (NDV) have generally been described as mild to moderate in severity. As noted previously (refer to the General Information section of this summary for more information), NDV has been reported to cause mild flu-like symptoms, conjunctivitis, and laryngitis in humans. [1–10]

The most commonly reported side effect after treatment of cancer patients with the virus alone is fever, which usually subsides within 24 hours.[2,11,12] In one study of infectious virus, localized adverse effects, such as inflammation and edema, were observed in the vicinity of some tumors.[12] These adverse effects may have contributed to the death of one patient.[12] Other adverse effects reported in this study included fatigue, low blood pressure, shortness of breath, and hypoxia. Some of these adverse effects were serious enough to require hospitalization.

Mild headache, mild fever on the day of vaccination, and itching, swelling, and erythema at injection sites are the most commonly reported side effects following injection of NDV-infected whole cell vaccines.[13–17]

The only adverse effect associated with administration of NDV oncolysate vaccines is inflammation at injection sites.[18–20]

Most of the flu-like symptoms, fever, and edema observed in studies in which cytokines were combined with NDV oncolysates or whole cell vaccines have been attributed to treatment with interleukin-2.[18–22]

References

1. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb. [PUBMED Abstract]
2. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993. [PUBMED Abstract]
3. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for “therapeutic” viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994. [PUBMED Abstract]
4. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996. [PUBMED Abstract]
5. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994. [PUBMED Abstract]
6. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994. [PUBMED Abstract]
7. Batliwalla FM, Bateman BA, Serrano D, et al.: A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4 (12): 783-94, 1998. [PUBMED Abstract]
8. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992. [PUBMED Abstract]
9. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998. [PUBMED Abstract]
10. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996.
11. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964.
12. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002. [PUBMED Abstract]
13. Liebrich W, Schlag P, Manasterski M, et al.: In vitro and clinical characterisation of a Newcastle disease virus-modified autologous tumour cell vaccine for treatment of colorectal cancer patients. Eur J Cancer 27 (6): 703-10, 1991. [PUBMED Abstract]
14. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996. [PUBMED Abstract]
15. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990. [PUBMED Abstract]
16. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990. [PUBMED Abstract]
17. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992. [PUBMED Abstract]
18. Mallmann P, Eis-Hubinger AM, Krebs D: Lymphokine-activated tumor-infiltrating lymphocytes and autologous tumor vaccine in breast and ovarian cancer. Onkologie 15 (6): 490-6, 1992.
19. Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996. [PUBMED Abstract]
20. Kirchner HH, Anton P, Atzpodien J: Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 13 (3): 171-3, 1995. [PUBMED Abstract]
21. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN-alpha(2b). Int J Oncol 6 (5): 947-54, 1995. [PUBMED Abstract]
22. Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993. [PUBMED Abstract]

In view of the evidence accumulated, no conclusions can be drawn about the effectiveness of using Newcastle disease virus in the treatment of cancer. Most reported clinical studies have involved few patients, and historical control subjects rather than actual control groups have often been used for outcome comparisons. Poor descriptions of study design and incomplete reporting of clinical data have hindered evaluation of many of the reported findings. However, while most studies are small and lack adequate controls, the number of studies suggesting a potential clinical value warrants further attention.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

1. What is Newcastle disease virus?

   Newcastle disease virus (NDV) is a virus that causes a deadly infection in many kinds of birds. In humans, NDV causes mild flu-like symptoms or conjunctivitis (an infection of the eye that is also called pink eye) and/or laryngitis (an irritation and swelling of the voice box and the area around it).

   Like other viruses, NDV infects cells (called host cells) and then uses those cells to replicate (make copies of) itself. Researchers are interested in NDV because it replicates itself more quickly in human cancer cells than in most normal human cells and it can kill the host cells. For these reasons, the virus is being studied as a treatment for cancer.

2. What is the history of the discovery and use of Newcastle disease virus as a complementary or alternative treatment for cancer?

   The first report that NDV may be useful as a cancer treatment was published in 1964. For 20 years before this report, NDV was used in a vaccine to prevent Newcastle disease in birds. During that time, it was learned that NDV caused only minor illness in humans. The mild side effects caused by NDV in humans and its ability to replicate up to 10,000 times faster in human cancer cells than in most normal human cells, led complementary and alternative medicine researchers to look more closely at NDV as a possible cancer treatment. NDV is now being studied by conventional medicine researchers also.

3. What is the theory behind the claim that Newcastle disease virus is useful in treating cancer?

   There are many strains of NDV, and they may be either lytic or nonlytic for human cells. Lytic strains kill the infected cell by damaging its outer membrane (layer of tissue). Nonlytic strains kill by blocking the basic processes a cell needs to live. Lytic strains of NDV have been studied in humans because they can kill cancer cells directly, but both lytic and nonlytic strains have been used to make vaccines to help the immune system fight cancer.

4. How is Newcastle disease virus administered?

   The way NDV is given depends on how the virus is used to target cancer cells. It may be used to directly infect the patient with NDV or to make cancer vaccines. Cancer vaccines made with NDV may improve the body’s natural immune response to cancer, causing it to attack and kill more cancer cells than it would if the NDV were not present. Researchers are studying 3 ways of using NDV as a possible cancer treatment:

   • Infection of the cancer patient with NDV

     NDV can be injected directly into the tumor, a muscle, or a vein (intravenous injection), or into the colon. The virus can also be inhaled. As explained in Question 1, NDV infects cells and then replicates itself, creating more copies of the virus that can then infect cells throughout the body. This process targets and kills cancer cells by damaging the cells’ outer membranes.

   • Oncolysate vaccine

     Oncolysate vaccines are made using pieces of cancer cell membranes infected with NDV. Oncolysate-based vaccines are injected under or into the skin.

   • Whole-cell vaccine

     Whole-cell vaccines are made using whole tumor cells infected with NDV. The tumor cells used in the vaccine are changed in the laboratory so that they cannot multiply or infect the patient. Whole-cell vaccines with NDV are given only by injection under the skin.

5. Have any preclinical (laboratory or animal) studies been conducted using Newcastle disease virus?

   A number of preclinical studies have been done with NDV. Research in a laboratory or using animals is done to find out if a drug, procedure, or treatment is likely to be useful in humans. These preclinical studies are done before any testing in humans is begun. The following has been learned from preclinical studies:

   • NDV replicates more quickly in human cancer cells than in any other type of cell.
   • Some types of NDV are able to directly kill certain types of cancer cells.
   • NDV and NDV-infected cancer cells can cause the immune system to respond in different ways.

   A few of these studies used human cells, but most used animal cells. Based on these and other laboratory findings, clinical trials (research studies with people) using NDV were begun.

6. Have any clinical trials (research studies with people) of NDV been conducted?

   Clinical trials of NDV have been done but have not proven that NDV is effective as a cancer treatment. Some of the trials reported positive results and some did not. Most of the studies enrolled only small numbers of patients who also received standard treatments. None of the trials published in English were randomized and few were controlled. Randomized clinical trials give the highest level of evidence. In randomized trials, volunteers are assigned randomly (by chance) to one of 2 or more groups that compare different factors related to the treatment. In a controlled clinical trial, one group (called the control group) does not receive the new treatment being studied. The control group is then compared to the groups that receive the new treatment, to see if the new treatment works. Randomized controlled trials, enrolling larger numbers of people, are needed to confirm the results of studies done so far on the use of NDV to treat cancer.

   Clinical trials studying the use of NDV as a cancer treatment have been done in the United States, Canada, China, Germany, and Hungary. Below are brief descriptions of these studies.

   Studies Using Oncolysate Vaccines

   Four clinical trials in the United States studied the use of NDV oncolysates in patients with metastatic melanoma. Three of these studies, a phase I clinical trial and 2 phase II clinical trials, were by the same group of researchers. Some positive results were found in these studies. The fourth trial was led by different researchers and showed no benefit. The same type of NDV was used to make the vaccines in all 4 studies, but the 2 groups of researchers used different methods to make them. Results from these studies need to be confirmed by randomized controlled trials that enroll larger numbers of people.

   Two other phase II trials of NDV oncolysates were done in Germany. One of the studies showed that people in the trial had longer disease-free survival when compared with published information on similar patients who were treated with surgery alone. Because these studies were not controlled and the patients received other treatments, it is not clear if it was the treatment with NDV oncolysates that caused the responses reported.

   Studies Using Whole-cell Vaccines

   Most of the published clinical studies of whole-cell vaccines with NDV have been done in Germany. The largest reported trial was in China. Most of these studies involved patients with colorectal cancer, breast cancer, ovarian cancer, renal cell (kidney) cancer, or malignant glioma. The same type of NDV was used to make the vaccines in all of the studies.

   Some of these studies found improved disease-free survival or improved overall survival in patients treated with whole-cell vaccines. The lack of control groups and other weaknesses in study design and reporting made it unclear if benefits were caused by the whole-cell vaccine or by something else. Overall, the results showed that these vaccines may help the immune system kill more cancer cells during the vaccination program but may not provide long-term cancer immunity.

   Studies Involving Infection with NDV (Including MTH-68)

   Most research on the treatment of cancer by infecting patients with NDV has been done in Hungary, using the NDV strain MTH-68. The published findings include the following types of studies:

   • An anecdotal report (incomplete descriptions of the medical and treatment history of one or more patients).
   • A case report (a detailed report of the diagnosis, treatment, and follow-up of an individual patient).
   • A small case series (a group of case reports involving patients who were given similar treatment).
   • A phase II clinical trial.

   According to the researchers, the MTH-68 treatment was helpful for most of the patients in these studies. The number of patients in the studies was small, however, and the patients in the clinical trial were not randomly assigned. The patients also received other treatments. For these reasons, it is not known if the patients were helped by the MTH-68 or by something else.

   In the United States, a phase I clinical trial tested PV701, another type of NDV. In this trial, 79 patients with advanced cancers that were not helped by conventional therapy were given PV701 by injection into a vein. Some patients had partial responses to the treatment, while others did not have any change in their condition. More studies are planned.

   One major concern is that repeated injections of NDV may cause a person’s immune system to form antibodies against the virus. These antibodies would prevent NDV from infecting and killing cancer cells. More research is needed to study this.

   While most studies of NDV in cancer treatment have been small and without control groups, there have been enough promising results to call for continued research.

7. Have any side effects or risks been reported from NDV?

   The side effects caused by NDV exposure have been mild to moderate. As noted in Question 1, NDV causes mild flu-like symptoms, conjunctivitis, and laryngitis in humans. Other side effects vary with how the virus is given.

   • The most commonly reported side effect after treatment with the virus alone is fever, which usually goes away within 24 hours. In one study, inflammation and swelling were seen near some tumors. These complications may have contributed to the death of one patient.
   • The most common side effects of treatment with NDV-infected whole-cell vaccines are minor:
     • Mild headache.
     • Mild fever on the day of the vaccination.
     • Itching, swelling, and redness of the skin at the injection site.
   • The only negative effect of treatment with the NDV oncolysate vaccine is inflammation at the injection site.

   Studies that combined treatment with NDV oncolysates or whole-cell vaccines with substances called cytokines reported flu-like symptoms, fever, and swelling. The side effects seen in these studies have been linked to the cytokine portion of the treatment.

8. Is Newcastle disease virus approved by the US Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The US Food and Drug Administration (FDA) has not approved Newcastle disease virus as a treatment for cancer.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include:

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of milk thistle as a treatment and adjunct agent for people with cancer.

The summary includes a brief history of milk thistle, a review of the laboratory studies and clinical trials, and a description of adverse effects associated with milk thistle use.

This summary contains the following key information:

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

The botanical name for milk thistle is Silybum marianum (L.) Gaertn. Milk thistle is also referred to as the following:[1]

The plant is indigenous to Europe but can also be found in the United States and South America. Traditionally, the leaves have been used in salads, and the fruit of the flower has been roasted as a coffee substitute. The seed-like fruits (achenes) of milk thistle are the medicinal parts of the plant.[1] The active constituent of milk thistle is silymarin, which is a complex mixture of flavonoids and flavonoid derivatives, the flavonolignans. The major constituents of silymarin are the three diastereomeric pairs, silybins A and B (also called silibinin), isosilybins A and B, silychristin, isosilychristin, and silydianin.[2,3] Most supplements are standardized according to their silybin content. Special formulations of silymarin and/or the silybins have been developed to enhance their bioavailability by conjugation with phosphatidylcholine. Because of the lipophilic nature of its active constituents, milk thistle is usually administered as an extract in capsule or tablet form rather than as an herbal tea. In Europe, silybin is administered intravenously as the only effective antidote for Amanita phalloides (Fr.).[4] Humans exposed to this mushroom toxin develop serious liver failure that progresses to death.

Several companies distribute milk thistle as a dietary supplement. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because dietary supplements are not formally reviewed for manufacturing consistency, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of milk thistle as a treatment for cancer or any other medical condition.

Despite milk thistle’s long history of being used to treat liver and biliary complaints, it was not until 1968 that silymarin was isolated from the seeds of the plant, and it was proposed that silymarin might be the active ingredient.[5] Researchers have investigated the role that silibinin may play in the treatment of hepatitis and cirrhosis. Most studies have investigated the isolated compound silymarin or its most active isomer silybin, rather than the herbal plant in its whole form.

Silymarin is most well known for its purported effects on the liver. In laboratory studies, silymarin has been found to stabilize cell membranes, thus preventing toxic chemicals from entering the cell.[4,6–8] Laboratory studies have also demonstrated that silymarin stimulates synthesis and activity of enzymes responsible for detoxification pathways.[7–18] Specifically, silymarin has been shown to stimulate the glutathione S-transferase pathway and alter the intracellular concentration of glutathione (a potent antioxidant). Silymarin has also been shown to neutralize a wide range of free radicals. Reports that associate the flavonolignans with potential estrogenic effect (e.g., via mediation of the estrogen receptor) are sparse and currently not supported by in vitro or in vivo experimental evidence.[19]

Laboratory experiments conducted using cancer cell lines have suggested that silibinin enhances the efficacy of cisplatin and doxorubicin against ovarian and breast cancer cells.[20] Silybin appears to have direct anticancer effects against prostate, breast, and ectocervical tumor cells.[21] Silybin may also affect the cell cycle in cancer cells by slowing down cell growth, as demonstrated with prostate cancer cell lines.[22] Laboratory studies using leukemia cell lines found that silybin did not stimulate growth of leukemia cells.[23]

Most clinical trials have investigated silymarin’s effectiveness in the treatment of patients with hepatitis, cirrhosis, or biliary disorders.[24–33] These studies have employed a wide range of doses (120–560 mg/day) and have yielded conflicting results.[34,35] The most commonly reported adverse effects are a mild laxative effect and gastrointestinal upset.

References

1. PDR® for Herbal Medicines™. 2nd ed. Medical Economics, 2000.
2. Lee DY, Liu Y: Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk thistle). J Nat Prod 66 (9): 1171-4, 2003. [PUBMED Abstract]
3. Napolitano JG, Lankin DC, Graf TN, et al.: HiFSA fingerprinting applied to isomers with near-identical NMR spectra: the silybin/isosilybin case. J Org Chem 78 (7): 2827-39, 2013. [PUBMED Abstract]
4. Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983. [PUBMED Abstract]
5. Wagner H, Hörhammer L, Münster R: [On the chemistry of silymarin (silybin), the active principle of the fruits from Silybum marianum (L.) Gaertn. (Carduus marianus L.)] Arzneimittelforschung 18 (6): 688-96, 1968. [PUBMED Abstract]
6. Campos R, Garrido A, Guerra R, et al.: Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55 (5): 417-9, 1989. [PUBMED Abstract]
7. Farghali H, Kameniková L, Hynie S, et al.: Silymarin effects on intracellular calcuim and cytotoxicity: a study in perfused rat hepatocytes after oxidative stress injury. Pharmacol Res 41 (2): 231-7, 2000. [PUBMED Abstract]
8. Lettéron P, Labbe G, Degott C, et al.: Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem Pharmacol 39 (12): 2027-34, 1990. [PUBMED Abstract]
9. Zhao J, Agarwal R: Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 20 (11): 2101-8, 1999. [PUBMED Abstract]
10. Valenzuela A, Guerra R, Videla LA: Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3: comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Med (6): 438-40, 1986. [PUBMED Abstract]
11. Valenzuela A, Guerra R, Garrido A: Silybin dihemisuccinate protects rat erythrocytes against phenylhydrazine-induced lipid peroxidation and hemolysis. Planta Med 53 (5): 402-5, 1987. [PUBMED Abstract]
12. Valenzuela A, Aspillaga M, Vial S, et al.: Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med 55 (5): 420-2, 1989. [PUBMED Abstract]
13. Mira ML, Azevedo MS, Manso C: The neutralization of hydroxyl radical by silibin, sorbinil and bendazac. Free Radic Res Commun 4 (2): 125-9, 1987. [PUBMED Abstract]
14. Mira L, Silva M, Manso CF: Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharmacol 48 (4): 753-9, 1994. [PUBMED Abstract]
15. Koch HP, Löffler E: Influence of silymarin and some flavonoids on lipid peroxidation in human platelets. Methods Find Exp Clin Pharmacol 7 (1): 13-8, 1985. [PUBMED Abstract]
16. Garrido A, Arancibia C, Campos R, et al.: Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: its probable antioxidant effect is potentiated by the flavonoid silybin. Pharmacol Toxicol 69 (1): 9-12, 1991. [PUBMED Abstract]
17. Bosisio E, Benelli C, Pirola O: Effect of the flavanolignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. Pharmacol Res 25 (2): 147-54, 1992 Feb-Mar. [PUBMED Abstract]
18. Altorjay I, Dalmi L, Sári B, et al.: The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung 80 (1-4): 375-80, 1992. [PUBMED Abstract]
19. El-Shitany NA, Hegazy S, El-Desoky K: Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine 17 (2): 116-25, 2010. [PUBMED Abstract]
20. Scambia G, De Vincenzo R, Ranelletti FO, et al.: Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 32A (5): 877-82, 1996. [PUBMED Abstract]
21. Bhatia N, Zhao J, Wolf DM, et al.: Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 147 (1-2): 77-84, 1999. [PUBMED Abstract]
22. Zi X, Agarwal R: Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96 (13): 7490-5, 1999. [PUBMED Abstract]
23. Duthie SJ, Johnson W, Dobson VL: The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimdines) and growth in human cells. Mutat Res 390 (1-2): 141-51, 1997. [PUBMED Abstract]
24. Vailati A, Aristia L, Sozzé E, et al.: Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64 (3), 219-28, 1993.
25. Salmi HA, Sarna S: Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17 (4): 517-21, 1982. [PUBMED Abstract]
26. Parés A, Planas R, Torres M, et al.: Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 28 (4): 615-21, 1998. [PUBMED Abstract]
27. Moscarella S, Giusti A, Marra F, et al.: Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholine complex in chronic liver disease: preliminary results. Current Therapeutic Research 53 (1): 98-102.
28. Marena C, Lampertico M: Preliminary clinical development of silipide: a new complex of silybin in toxic liver disorders. Planta Med 57 (Suppl 2): A124-5, 1991.
29. Marcelli R, Bizzoni P, Conte D, et al.: Randomized controlled study of the efficacy and tolerability of a short course of IdB 1016 in the treatment of chronic persistent hepatitis. European Bulletin of Drug Research 1 (3): 131-5, 1992.
30. Flisiak R, Prokopowicz D: Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 44 (17): 1419-25, 1997 Sep-Oct. [PUBMED Abstract]
31. Ferenci P: [Therapy of chronic hepatitis C] Wien Med Wochenschr 150 (23-24): 481-5, 2000. [PUBMED Abstract]
32. Buzzelli G, Moscarella S, Giusti A, et al.: Therapeutic effects of a new silybin complex in chronic active hepatitis (CAH). [Abstract] Hellenic Journal of Gastroenterology 5 (Suppl): A-151, 38, 1992.
33. Albrecht M, Frerick H, Kuhn U, et al.: Therapy of toxic liver pathologies with Legalon®. Z Klin Med 47: 87-92, 1992.
34. Rambaldi A, Jacobs BP, Gluud C: Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev (4): CD003620, 2007. [PUBMED Abstract]
35. Yang Z, Zhuang L, Lu Y, et al.: Effects and tolerance of silymarin (milk thistle) in chronic hepatitis C virus infection patients: a meta-analysis of randomized controlled trials. Biomed Res Int 2014: 941085, 2014. [PUBMED Abstract]

Milk thistle has been used for more than 2,000 years, primarily as a treatment for liver dysfunction. The oldest reported use of milk thistle was by Dioscorides (A.D. 40–90), who recommended the herb as a treatment for serpent bites.[1] Pliny the Elder (A.D. 23–79) reported that the juice of the plant mixed with honey is indicated for “carrying off bile.”[1,2] In the Middle Ages, milk thistle was revered as an antidote for liver toxins.[1,2] The British herbalist Culpepper reported milk thistle to be effective for relieving obstructions of the liver.[1,2] In 1898, eclectic physicians Felter and Lloyd stated the herb was good for congestion of the liver, spleen, and kidney.[1,2] American Indian or Alaska Native people use milk thistle to treat boils and other skin diseases. Homeopathic practitioners use preparations from the seeds to treat jaundice, gallstones, peritonitis, hemorrhage, bronchitis, and varicose veins.[2] The German Commission E recommends milk thistle use for dyspeptic complaints, toxin-induced liver damage, hepatic cirrhosis, and as a supportive therapy for chronic inflammatory liver conditions.[3]

References

1. Flora K, Hahn M, Rosen H, et al.: Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 93 (2): 139-43, 1998. [PUBMED Abstract]
2. Foster S: Milk Thistle: Silybum marianum. Rev. ed. American Botanical Council, 1999.
3. Blumenthal M, Busse WR, et al., eds.: The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. American Botanical Council, 1998.

Research studies conducted in the laboratory have investigated the properties of silymarin or its isomer silybin using cell lines and animal models. Other substances in milk thistle have not been extensively studied.

Several research studies have investigated the effects of silymarin or silybin in a noncancer context. These studies have tested silymarin or silybin:

Silymarin or silybin has also been investigated in cancer models. The effects of silymarin and/or silybin have been investigated in the following cell lines:

In animal tumor models, tongue cancer,[17] skin cancer,[18–23] bladder cancer,[24] and adenocarcinoma of the colon [25,26] and small intestine [26] have been investigated. These studies have tested the ability of silymarin or silibinin to:

Laboratory data suggest that silymarin and silybin protect the liver from damage induced by toxic chemicals. Animal studies have found that liver cells treated with silybin and then exposed to toxins do not incur cell damage or death at the same rate as liver cells that are not treated with silybin. This finding suggests that silybin can prevent toxins from entering the cell or effectively exports toxins out of the cell before damage ensues.[11,27–31] Alternatively, this may be related to the effect of silymarin on detoxification systems. In vitro data have shown silybin to stimulate and/or inhibit phase I detoxification pathways in silybin-treated human liver cells. However, this effect was found to be dose-dependent, and these levels are not physiologically attainable with the current manufacturer dose recommendations.[32,33]

Silymarin and silybin have also been found to accelerate cell regeneration in the liver through stimulation of precursors to DNA synthesis and enhancement of production of the cellular enzymes required for DNA synthesis.[34–39] Silymarin has been shown to mitigate oxidative stress in cells treated with pro-oxidant compounds.[40]

While some reports exist about the estrogenic effects assigned to silybin and silybin-containing materials,[41] the observed effects are moderate, and the molecular mechanisms are not yet understood. Some evidence exists about the positive impact of these milk thistle compounds on bone density in rats and mice that have undergone ovariectomy.[42]

Silibinin inhibits prostate cancer cell–induced osteoclastogenesis, suggesting that silibinin may be useful clinically for the treatment of bone metastases. Silibinin targets prostate cancer cell–induced osteoclast differentiation and activity of murine macrophage cells.[43]

Although many of these studies have produced encouraging results, none of the findings have been replicated in human clinical trials.

Several in vitro studies have explored anticancer effects of milk thistle extracts. Silybinin has been shown to inhibit cell proliferation by inducing cell cycle arrest at the G1 and G2-M transition in epidermal,[7,44,45] prostate,[7] breast,[7] and cervical [7] cancer cell lines. One study also demonstrated that growth of colon cancer cell lines was inhibited by silibinin, apparently through suppression of NF-kappa B.[46] Finally, silymarin has also been shown to induce differentiation in a human leukemia cell line.[15]

Other in vitro studies have demonstrated that components of milk thistle extract can enhance the effects of certain cytotoxic agents against various cancer types (i.e., etoposide against LN229 glioma cells,[50] cisplatin against A2780 ovarian cancer cells [13,51] and MCF-7 breast cancer cells,[13] and tumor necrosis factor alpha against DU145 prostate cancer cells [52]).

References

1. Zi X, Agarwal R: Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96 (13): 7490-5, 1999. [PUBMED Abstract]
2. Singh RP, Dhanalakshmi S, Tyagi AK, et al.: Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res 62 (11): 3063-9, 2002. [PUBMED Abstract]
3. Zi X, Zhang J, Agarwal R, et al.: Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res 60 (20): 5617-20, 2000. [PUBMED Abstract]
4. Zi X, Grasso AW, Kung HJ, et al.: A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res 58 (9): 1920-9, 1998. [PUBMED Abstract]
5. Sharma Y, Agarwal C, Singh AK, et al.: Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol Carcinog 30 (4): 224-36, 2001. [PUBMED Abstract]
6. Flaig TW, Glodé M, Gustafson D, et al.: A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate 70 (8): 848-55, 2010. [PUBMED Abstract]
7. Bhatia N, Zhao J, Wolf DM, et al.: Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 147 (1-2): 77-84, 1999. [PUBMED Abstract]
8. Jiang C, Agarwal R, Lü J: Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun 276 (1): 371-8, 2000. [PUBMED Abstract]
9. Zi X, Feyes DK, Agarwal R: Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. Clin Cancer Res 4 (4): 1055-64, 1998. [PUBMED Abstract]
10. Saliou C, Rihn B, Cillard J, et al.: Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways. FEBS Lett 440 (1-2): 8-12, 1998. [PUBMED Abstract]
11. Shear NH, Malkiewicz IM, Klein D, et al.: Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol 8 (6): 279-91, 1995. [PUBMED Abstract]
12. Duthie SJ, Johnson W, Dobson VL: The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimdines) and growth in human cells. Mutat Res 390 (1-2): 141-51, 1997. [PUBMED Abstract]
13. Scambia G, De Vincenzo R, Ranelletti FO, et al.: Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 32A (5): 877-82, 1996. [PUBMED Abstract]
14. Manna SK, Mukhopadhyay A, Van NT, et al.: Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol 163 (12): 6800-9, 1999. [PUBMED Abstract]
15. Kang SN, Lee MH, Kim KM, et al.: Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochem Pharmacol 61 (12): 1487-95, 2001. [PUBMED Abstract]
16. Clinton SK: The dietary antioxidant network and prostate carcinoma. Cancer 86 (9): 1629-31, 1999. [PUBMED Abstract]
17. Yanaida Y, Kohno H, Yoshida K, et al.: Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis 23 (5): 787-94, 2002. [PUBMED Abstract]
18. Agarwal R, Katiyar SK, Lundgren DW, et al.: Inhibitory effect of silymarin, an anti-hepatotoxic flavonoid, on 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and mRNA in SENCAR mice. Carcinogenesis 15 (6): 1099-103, 1994. [PUBMED Abstract]
19. Katiyar SK, Korman NJ, Mukhtar H, et al.: Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 89 (8): 556-66, 1997. [PUBMED Abstract]
20. Lahiri-Chatterjee M, Katiyar SK, Mohan RR, et al.: A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res 59 (3): 622-32, 1999. [PUBMED Abstract]
21. Singh RP, Tyagi AK, Zhao J, et al.: Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis 23 (3): 499-510, 2002. [PUBMED Abstract]
22. Zhao J, Sharma Y, Agarwal R: Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion. Mol Carcinog 26 (4): 321-33, 1999. [PUBMED Abstract]
23. Zhao J, Lahiri-Chatterjee M, Sharma Y, et al.: Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis 21 (4): 811-6, 2000. [PUBMED Abstract]
24. Vinh PQ, Sugie S, Tanaka T, et al.: Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Jpn J Cancer Res 93 (1): 42-9, 2002. [PUBMED Abstract]
25. Kohno H, Tanaka T, Kawabata K, et al.: Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer 101 (5): 461-8, 2002. [PUBMED Abstract]
26. Gershbein LL: Action of dietary trypsin, pressed coffee oil, silymarin and iron salt on 1,2-dimethylhydrazine tumorigenesis by gavage. Anticancer Res 14 (3A): 1113-6, 1994 May-Jun. [PUBMED Abstract]
27. Campos R, Garrido A, Guerra R, et al.: Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55 (5): 417-9, 1989. [PUBMED Abstract]
28. Farghali H, Kameniková L, Hynie S, et al.: Silymarin effects on intracellular calcuim and cytotoxicity: a study in perfused rat hepatocytes after oxidative stress injury. Pharmacol Res 41 (2): 231-7, 2000. [PUBMED Abstract]
29. Lettéron P, Labbe G, Degott C, et al.: Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem Pharmacol 39 (12): 2027-34, 1990. [PUBMED Abstract]
30. Valenzuela A, Guerra R, Garrido A: Silybin dihemisuccinate protects rat erythrocytes against phenylhydrazine-induced lipid peroxidation and hemolysis. Planta Med 53 (5): 402-5, 1987. [PUBMED Abstract]
31. Campos R, Garrido A, Guerra R, et al.: Acetaminophen hepatotoxicity in rats is attenuated by silybin dihemisuccinate. Prog Clin Biol Res 280: 375-8, 1988. [PUBMED Abstract]
32. Zuber R, Modrianský M, Dvorák Z, et al.: Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 16 (7): 632-8, 2002. [PUBMED Abstract]
33. Venkataramanan R, Ramachandran V, Komoroski BJ, et al.: Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 28 (11): 1270-3, 2000. [PUBMED Abstract]
34. Sonnenbichler J, Mattersberger J, Rosen H: [Stimulation of RNA synthesis in rat liver and isolated hepatocytes by silybin, an antihepatotoxic agent from Silybum marianum L. Gaertn (author’s transl)] Hoppe Seylers Z Physiol Chem 357 (8): 1171-80, 1976. [PUBMED Abstract]
35. Sonnenbichler J, Zetl I: [Mechanism of action of silibinin. V. Effect of silibinin on the synthesis of ribosomal RNA, mRNA and tRNA in rat liver in vivo] Hoppe Seylers Z Physiol Chem 365 (5): 555-66, 1984. [PUBMED Abstract]
36. Sonnenbichler J, Zetl I: Biochemical effects of the flavonolignane silibinin on RNA, protein and DNA synthesis in rat livers. Prog Clin Biol Res 213: 319-31, 1986. [PUBMED Abstract]
37. Sonnenbichler J, Goldberg M, Hane L, et al.: Stimulatory effect of Silibinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malign cell lines. Biochem Pharmacol 35 (3): 538-41, 1986. [PUBMED Abstract]
38. Machicao F, Sonnenbichler J: Mechanism of the stimulation of RNA synthesis in rat liver nuclei by silybin. Hoppe Seylers Z Physiol Chem 358 (2): 141-7, 1977. [PUBMED Abstract]
39. Dehmlow C, Erhard J, de Groot H: Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 23 (4): 749-54, 1996. [PUBMED Abstract]
40. Malekinejad H, Rahmani F, Valivande-Azar S, et al.: Long-term administration of Silymarin augments proinflammatory mediators in the hippocampus of rats: evidence for antioxidant and pro-oxidant effects. Hum Exp Toxicol 31 (9): 921-30, 2012. [PUBMED Abstract]
41. El-Shitany NA, Hegazy S, El-Desoky K: Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine 17 (2): 116-25, 2010. [PUBMED Abstract]
42. Kim JL, Kim YH, Kang MK, et al.: Antiosteoclastic activity of milk thistle extract after ovariectomy to suppress estrogen deficiency-induced osteoporosis. Biomed Res Int 2013: 919374, 2013. [PUBMED Abstract]
43. Kavitha CV, Deep G, Gangar SC, et al.: Silibinin inhibits prostate cancer cells- and RANKL-induced osteoclastogenesis by targeting NFATc1, NF-κB, and AP-1 activation in RAW264.7 cells. Mol Carcinog 53 (3): 169-80, 2014. [PUBMED Abstract]
44. Zi X, Agarwal R: Modulation of mitogen-activated protein kinase activation and cell cycle regulators by the potent skin cancer preventive agent silymarin. Biochem Biophys Res Commun 263 (2): 528-36, 1999. [PUBMED Abstract]
45. Ahmad N, Gali H, Javed S, et al.: Skin cancer chemopreventive effects of a flavonoid antioxidant silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell cycle progression. Biochem Biophys Res Commun 247 (2): 294-301, 1998. [PUBMED Abstract]
46. Raina K, Agarwal C, Agarwal R: Effect of silibinin in human colorectal cancer cells: targeting the activation of NF-κB signaling. Mol Carcinog 52 (3): 195-206, 2013. [PUBMED Abstract]
47. Zi X, Mukhtar H, Agarwal R: Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha. Biochem Biophys Res Commun 239 (1): 334-9, 1997. [PUBMED Abstract]
48. Lee MH, Huang Z, Kim DJ, et al.: Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth. Cancer Prev Res (Phila) 6 (5): 455-65, 2013. [PUBMED Abstract]
49. Velmurugan B, Gangar SC, Kaur M, et al.: Silibinin exerts sustained growth suppressive effect against human colon carcinoma SW480 xenograft by targeting multiple signaling molecules. Pharm Res 27 (10): 2085-97, 2010. [PUBMED Abstract]
50. Elhag R, Mazzio EA, Soliman KF: The effect of silibinin in enhancing toxicity of temozolomide and etoposide in p53 and PTEN-mutated resistant glioma cell lines. Anticancer Res 35 (3): 1263-9, 2015. [PUBMED Abstract]
51. Giacomelli S, Gallo D, Apollonio P, et al.: Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin. Life Sci 70 (12): 1447-59, 2002. [PUBMED Abstract]
52. Dhanalakshmi S, Singh RP, Agarwal C, et al.: Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis. Oncogene 21 (11): 1759-67, 2002. [PUBMED Abstract]

Several small studies have investigated silymarin for its direct treatment of cancer or for its effects on treatment-related toxicity.

A phase I study was designed to determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction.[1] Three patients were enrolled in this single-institution trial. All patients who were enrolled consumed 2 g/d of the study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all three patients, liver function abnormalities and tumor marker alpha-fetoprotein progressed, but after day 56, the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All three patients died within 23 to 69 days of enrolling in the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly caused by the study drug. This patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

In a double-blind, placebo-controlled trial, 50 children who were undergoing treatment for acute lymphoblastic leukemia, and who had chemotherapy-related hepatotoxicity, were randomly assigned to receive silymarin or placebo for a 4-week period.[2] Four weeks after completion of the intervention, the silymarin group had a significantly lower aspartate aminotransferase (AST) (P = .05) and a trend towards a significantly lower alanine aminotransferase (ALT) (P = .07). Fewer chemotherapy dose reductions were observed in the silymarin group compared with the placebo group; however, the difference was not significant. No adverse events were reported.

A randomized placebo-controlled study of 37 men, who had a status of post–radical prostatectomy, investigated whether a 6-month daily administration of a silymarin and selenium combination would alter basic clinical chemistry, oxidative stress markers, and improve the quality-of-life (QOL) score in men after radical prostatectomy.[3] The 6-month daily administration of silymarin and selenium improved the QOL score, decreased low-density lipoproteins and total cholesterol, and increased serum selenium levels. The combination had no effect on blood antioxidant status and no influence on testosterone level. No adverse events were recorded. No improvement was found in the placebo group.

Another randomized placebo-controlled study of 30 patients with head and neck cancer investigated a 6-week course of silymarin for the prevention of radiation therapy–associated mucositis. Mucositis scores (World Health Organization, National Cancer Institute Common Toxicity Criteria) were significantly lower in the silymarin group.[4] Delay in progression to mucositis was also observed.

In a nonrandomized observational trial of 101 women with breast cancer who had undergone breast-conserving surgery followed by radiation therapy with 50.4 Gy plus a boost of 9 Gy to 16 Gy, a silymarin-based cream (Leviaderm) was tested in 51 women compared with panthenol-containing cream, the standard of care (SOC), which was given interventionally if local skin lesions occurred and administered to 50 women.[5] The acute skin reactions were classified according to the Radiation Therapy Oncology Group and visual analog scale scores. The median time to toxicity was prolonged significantly with the silymarin-based cream (45 vs. 29 days [SOC], P < .0001). Only 9.8% of patients using the silymarin-based cream showed grade 2 toxicity in week 5 of radiation therapy, compared with 52% in the SOC group. At the end of radiation therapy, 23.5% of the women in the silymarin-based study group developed no skin reactions compared with 2% of the women in the SOC group, while grade 3 toxicity occurred in only 2% of women in the silymarin-based group and in 28% of women in the SOC group.

References

1. Siegel AB, Narayan R, Rodriguez R, et al.: A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma. Integr Cancer Ther 13 (1): 46-53, 2014. [PUBMED Abstract]
2. Ladas EJ, Kroll DJ, Oberlies NH, et al.: A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Cancer 116 (2): 506-13, 2010. [PUBMED Abstract]
3. Vidlar A, Vostalova J, Ulrichova J, et al.: The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy – a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154 (3): 239-44, 2010. [PUBMED Abstract]
4. Elyasi S, Hosseini S, Niazi Moghadam MR, et al.: Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phytother Res 30 (11): 1879-1885, 2016. [PUBMED Abstract]
5. Becker-Schiebe M, Mengs U, Schaefer M, et al.: Topical use of a silymarin-based preparation to prevent radiodermatitis : results of a prospective study in breast cancer patients. Strahlenther Onkol 187 (8): 485-91, 2011. [PUBMED Abstract]
6. Vailati A, Aristia L, Sozzé E, et al.: Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64 (3), 219-28, 1993.
7. Salmi HA, Sarna S: Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17 (4): 517-21, 1982. [PUBMED Abstract]
8. Parés A, Planas R, Torres M, et al.: Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 28 (4): 615-21, 1998. [PUBMED Abstract]
9. Flisiak R, Prokopowicz D: Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 44 (17): 1419-25, 1997 Sep-Oct. [PUBMED Abstract]
10. Angulo P, Patel T, Jorgensen RA, et al.: Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 32 (5): 897-900, 2000. [PUBMED Abstract]
11. Ferenci P, Dragosics B, Dittrich H, et al.: Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 9 (1): 105-13, 1989. [PUBMED Abstract]
12. Lucena MI, Andrade RJ, de la Cruz JP, et al.: Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. Int J Clin Pharmacol Ther 40 (1): 2-8, 2002. [PUBMED Abstract]
13. Velussi M, Cernigoi AM, De Monte A, et al.: Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 26 (4): 871-9, 1997. [PUBMED Abstract]
14. Seeff LB, Curto TM, Szabo G, et al.: Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology 47 (2): 605-12, 2008. [PUBMED Abstract]
15. Palasciano G, Portincasa P, Palmieri V, et al.: The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving long-term treatment with psychotropic drugs. Current Therapeutic Research 55 (5): 537-45.
16. Magliulo E, Gagliardi B, Fiori GP: [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres (author’s transl)] Med Klin 73 (28-29): 1060-5, 1978. [PUBMED Abstract]
17. Freedman ND, Curto TM, Morishima C, et al.: Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther 33 (1): 127-37, 2011. [PUBMED Abstract]
18. Azzam HS, Goertz C, Fritts M, et al.: Natural products and chronic hepatitis C virus. Liver Int 27 (1): 17-25, 2007. [PUBMED Abstract]
19. Polyak SJ, Morishima C, Shuhart MC, et al.: Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology 132 (5): 1925-36, 2007. [PUBMED Abstract]
20. Ferenci P, Scherzer TM, Kerschner H, et al.: Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 135 (5): 1561-7, 2008. [PUBMED Abstract]
21. Hawke RL, Schrieber SJ, Soule TA, et al.: Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol 50 (4): 434-49, 2010. [PUBMED Abstract]
22. Fried MW, Navarro VJ, Afdhal N, et al.: Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA 308 (3): 274-82, 2012. [PUBMED Abstract]
23. Albrecht M, Frerick H, Kuhn U, et al.: Therapy of toxic liver pathologies with Legalon®. Z Klin Med 47: 87-92, 1992.
24. Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983. [PUBMED Abstract]
25. Enjalbert F, Rapior S, Nouguier-Soulé J, et al.: Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 40 (6): 715-57, 2002. [PUBMED Abstract]
26. Moayedi B, Gharagozloo M, Esmaeil N, et al.: A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in β-thalassemia major patients receiving desferrioxamine. Eur J Haematol 90 (3): 202-9, 2013. [PUBMED Abstract]

Human studies of silymarin have shown minimal adverse effects in multiple large, blinded, placebo-controlled, randomized studies. Silymarin is well tolerated, with only rare reports of a mild laxative effect. Mild allergic reactions have been seen at high doses (>1,500 mg/day), although the details of these allergic reactions were not reported.[1] A case report from Australia described a reaction to a milk thistle extract that included intermittent episodes of sweating, abdominal cramping, nausea, vomiting, diarrhea, and weakness.[2] All symptoms resolved when the silymarin was discontinued. The authors suggested that the capsules were contaminated; the type of contamination was unknown.

According to the German Commission E, there are no reported side effects with milk thistle when the recommended doses are used. Rare cases of milk thistle producing a laxative effect have been reported. Human studies have reported stomach upset, heartburn, and transient headaches; however, none of these symptoms were attributed to supplementation with milk thistle, and supplementation was not discontinued.[3] One human dosing study reported nausea, heartburn, and dyspepsia in patients treated with 160 mg/day, dyspepsia in patients treated with 240 mg/day, and postprandial nausea and meteorism in patients treated with 360 mg/day. None of these side effects were dose related.

Silymarin has been well tolerated in high doses. Silymarin has been used in pregnant women with intrahepatic cholestasis at doses of 560 mg/day for 16 days, with no toxicity to the patient or the fetus.[4] The published data on silymarin use in children focuses on intravenous doses of 20 to 50 mg/kg of body weight for mushroom poisoning.[5] Silymarin has also proved nontoxic in rats and mice when administered in doses as high as 5,000 mg/kg of body weight. Rats and dogs have received silymarin at doses of 50 to 2,500 mg/kg of body weight for a 12-month period. Investigations, including postmortem analyses, showed no evidence of toxicity.

It is not known whether milk thistle may reduce, enhance, or have no impact on the effectiveness of chemotherapy. In vitro studies show that silymarin decreases the components of the cytochrome P450 enzyme system, which is involved in the clearance of certain chemotherapy drugs.[6] However, the dose at which inhibition is observed is high and not achieved with oral intake of silymarin.[7] One study investigated the effects of silymarin on the pharmacokinetics of irinotecan. Oral administration of milk thistle (200 mg, a clinically relevant dose, 3 times per day) had no significant effects on the pharmacokinetics of irinotecan. The authors concluded that the recommended doses of milk thistle are too low to affect activity of CYP3A4 or UGT1A1 enzyme pathways.[8]

Theoretically, milk thistle may also interact adversely with chemotherapy drugs that exert their cytotoxic effects through the generation of free radicals. Silymarin and its metabolite inhibit p-glycoprotein–mediated cellular efflux, leading to the potentiation of doxorubicin cytotoxicity.[9] No trials have been performed to support or negate these theoretical considerations. No effects on indinavir and alcohol pharmacokinetics have been observed. Enhancement of the antiarrhythmic effects of amiodarone in rats has been observed.[9]

References

1. PDR® for Herbal Medicines™. 2nd ed. Medical Economics, 2000.
2. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Adverse Drug Reactions Advisory Committee. Med J Aust 170 (5): 218-9, 1999. [PUBMED Abstract]
3. Vailati A, Aristia L, Sozzé E, et al.: Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64 (3), 219-28, 1993.
4. Hernández R, Nazar E: [Effect of silymarin in intrahepatic cholestasis of pregnancy (preliminary communication)] Rev Chil Obstet Ginecol 47 (1): 22-9, 1982. [PUBMED Abstract]
5. Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983. [PUBMED Abstract]
6. Venkataramanan R, Ramachandran V, Komoroski BJ, et al.: Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 28 (11): 1270-3, 2000. [PUBMED Abstract]
7. Zuber R, Modrianský M, Dvorák Z, et al.: Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 16 (7): 632-8, 2002. [PUBMED Abstract]
8. van Erp NP, Baker SD, Zhao M, et al.: Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 11 (21): 7800-6, 2005. [PUBMED Abstract]
9. Hu Z, Yang X, Ho PC, et al.: Herb-drug interactions: a literature review. Drugs 65 (9): 1239-82, 2005. [PUBMED Abstract]

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Given the limited amount of human data, the use of milk thistle/silymarin as a treatment for cancer patients cannot be recommended outside the context of well-designed clinical trials.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

1. What is milk thistle?

   Milk thistle is a plant whose fruit and seeds have been used for more than 2,000 years as a treatment for liver and bile duct disorders. Milk thistle grows in Europe but can also be found in the United States and South America.

   Silymarin, found in milk thistle seeds, is a mixture that contains compounds, such as silybin, isosilybin, silychristin and isosilychristin, silydianin, and taxifolin. Most studies have been done in silymarin or silybin, instead of the whole plant.

   The botanical name for milk thistle is Silybum marianum. Milk thistle is also called holy thistle, Marian thistle, Mary thistle, St. Mary thistle, Our Lady’s thistle, wild artichoke, Mariendistel (German), and Chardon-Marie (French).

2. How is milk thistle taken or given?

   Milk thistle is usually taken by mouth in capsules or tablets. In Europe silybin is given by intravenous infusion as the only treatment for Amanita phalloides, a mushroom toxin that causes death.

3. Have any laboratory or animal studies been done using milk thistle?

   In laboratory studies, tumor cells are used to test a substance to find out if it is likely to have any anticancer effects. In animal studies, tests are done to see if a drug, procedure, or treatment is safe and effective in animals. Laboratory and animal studies are done before a substance is tested in people.

   Laboratory and animal studies have tested the effects of milk thistle in laboratory experiments. Silymarin, the active substance found in milk thistle seeds, and silybin A and B, the major components of silymarin, have been studied in laboratory research. See the Laboratory/Animal/Preclinical Studies section of the health professional version of Milk Thistle for information on laboratory and animal studies done using milk thistle.

4. Have any studies of milk thistle been done in people?

   Several small studies have looked at whether milk thistle can be used to decrease side effects of cancer treatment.

   • A randomized clinical trial in children with acute lymphoblastic leukemia found that silymarin decreased the side effects of chemotherapy on the liver without harming the cancer treatment.
   • A randomized clinical trial in men with prostate cancer who had surgery to remove their prostate found that taking silymarin and selenium improved quality of life, lowered cholesterol, and increased the amount of selenium in the blood.
   • A randomized clinical trial of 30 patients with head and neck cancer who had radiation therapy found that those who took silymarin for 6 weeks had lower rates of radiation-related mucositis compared to those who did not.
   • A nonrandomized observational study in women with breast cancer who had surgery and radiation therapy found that a silymarin-based cream helped prevent patients from having skin rashes from radiation therapy.

   A number of clinical trials have studied milk thistle in the treatment of patients with hepatitis, cirrhosis, mushroom poisoning, or bile duct disorders. These trials have used a wide range of doses with mixed results. In a trial of biologic therapy for patients with chronic hepatitis, patients taking silymarin had less symptoms and a better quality of life compared to patients not taking silymarin.

   Silymarin has been found to help with iron chelation therapy, which removes extra iron in the blood of patients who have had many blood transfusions.

5. Have any side effects or risks been reported from milk thistle?

   Very few side effects from the use of milk thistle or silymarin have been reported. Several large studies in patients with liver disorders have found that taking silymarin may rarely have a laxative effect or cause nausea, heartburn, or stomach upset. At high doses, mild allergic reactions have been seen.

6. Is milk thistle approved by the U.S. Food and Drug Administration (FDA) for use as a cancer treatment in the United States?

   The U.S. Food and Drug Administration (FDA) has not approved the use of milk thistle as a treatment for cancer or any other medical condition.

   The FDA does not approve dietary supplements as safe or effective. The company that makes the dietary supplements is responsible for making sure they are safe and that the claims on the label are true and do not mislead the consumer. The way that supplements are made is not regulated by the FDA, so all batches and brands of milk thistle supplements may not be the same.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include:

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of laetrile as a treatment for people with cancer. The summary includes a history of laetrile research, a review of laboratory studies, the results of clinical trials, and possible side effects of laetrile use.

This summary contains the following key information:

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

The term laetrile is derived from the terms laevorotatory and mandelonitrile and is used to describe a purified form of the chemical amygdalin, a cyanogenic glucoside found in the pits of many fruits and raw nuts and in other plants, such as lima beans, clover, and sorghum.[1–6] In body fluids and at physiological pH, hydrogen cyanide dissolves to form the cyanide anion. The term vitamin B-17 was given to laetrile by E.T. Krebs Jr, but it is not an approved designation by the Committee on Nomenclature of the American Institute of Nutrition Vitamins. In the 1970s, laetrile gained popularity as an anticancer agent. By 1978, more than 70,000 individuals in the United States were reported to have been treated with it.[2,7,8]

Laetrile has been used for cancer treatment both as a single agent and in combination with a metabolic therapy program that consists of a specialized diet, high-dose vitamin supplements, and pancreatic enzymes.[9,10]

In the United States, researchers must file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to conduct drug research in human subjects. In 1970, an IND application to study laetrile was filed by the McNaughton Foundation (San Ysidro, California). This request was initially approved but later rejected because preclinical evidence in animals showed that laetrile was not likely to be effective as an anticancer agent,[3,11,12] and because there were questions about how the proposed study was to be conducted.[13] Laetrile supporters viewed this reversal as an attempt by the U.S. government to block access to new and promising cancer therapies, and pressure mounted to make laetrile available to the public. Court cases in Oklahoma, Massachusetts, New Jersey, and California challenged the FDA’s role in determining which drugs should be available to cancer patients. Consequently, laetrile was legalized in more than 20 states during the 1970s. In 1980, the U.S. Supreme Court acted to uphold a federal ban on interstate shipment of laetrile.[2,14] As a result, the use of laetrile has greatly diminished, but the compound continues to be manufactured and administered as an anticancer therapy, primarily in Mexico, and in some clinics in the United States.

Although the names laetrile, Laetrile, vitamin B-17, and amygdalin are often used interchangeably, they are not the same product. The chemical composition of U.S.-patented Laetrile (mandelonitrile-beta-glucuronide), a semisynthetic derivative of amygdalin, is different from the laetrile/amygdalin produced in Mexico (mandelonitrile beta-D-gentiobioside), which is made from crushed apricot pits.[15,16] Mandelonitrile, which contains a cyanide group, is a structural component of both products.[15] It has been proposed that released (hydrogen) cyanide is the active cancer-killing ingredient in laetrile, but two other breakdown products of amygdalin—prunasin (which is similar in structure to Laetrile) and benzaldehyde—may also be cancer cell inhibitors.[17–20] The studies discussed in this summary used either Mexican laetrile/amygdalin or the patented form. In most instances, the generic term laetrile will be used in this summary; however, a distinction will be made between the products when necessary.

Laetrile can be administered orally as a pill, or it can be given by injection (intravenous or intramuscular). It is commonly given intravenously for a period of time followed by oral maintenance therapy. The incidence of cyanide poisoning is much higher when laetrile is taken orally [21–23] because intestinal bacteria and some commonly eaten plants contain enzymes (beta-glucosidases) that activate the release of cyanide after laetrile has been ingested.[17,22] Relatively little breakdown occurs to yield the (hydrogen) cyanide when laetrile is injected.[7,22] Administration schedules and the length of treatment in animal models and humans vary widely.

References

1. Howard-Ruben J, Miller NJ: Unproven methods of cancer management. Part II: Current trends and implications for patient care. Oncol Nurs Forum 11 (1): 67-73, 1984 Jan-Feb. [PUBMED Abstract]
2. Curt GA: Unsound methods of cancer treatment. Princ Pract Oncol Updates 4 (12): 1-10, 1990.
3. Dorr RT, Paxinos J: The current status of laetrile. Ann Intern Med 89 (3): 389-97, 1978. [PUBMED Abstract]
4. Calabrese EJ: Possible adverse side effects from treatment with laetrile. Med Hypotheses 5 (9): 1045-9, 1979. [PUBMED Abstract]
5. The laetrile controversy. In: Moss RW: The Cancer Industry: The Classic Expose on the Cancer Establishment. First Equinox Press, 1996, pp 131-52.
6. Laetrile at Sloan-Kettering: a case study. In: Moss RW: The Cancer Industry: The Classic Expose on the Cancer Establishment. First Equinox Press, 1996, pp 153-86.
7. Lerner IJ: Laetrile: a lesson in cancer quackery. CA Cancer J Clin 31 (2): 91-5, 1981 Mar-Apr. [PUBMED Abstract]
8. Ellison NM, Byar DP, Newell GR: Special report on Laetrile: the NCI Laetrile Review. Results of the National Cancer Institute’s retrospective Laetrile analysis. N Engl J Med 299 (10): 549-52, 1978. [PUBMED Abstract]
9. Moertel CG, Fleming TR, Rubin J, et al.: A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N Engl J Med 306 (4): 201-6, 1982. [PUBMED Abstract]
10. Ross WE: Unconventional cancer therapy. Compr Ther 11 (9): 37-43, 1985. [PUBMED Abstract]
11. Lewis JP: Laetrile. West J Med 127 (1): 55-62, 1977. [PUBMED Abstract]
12. Unproven methods of cancer management. Laetrile. CA Cancer J Clin 22 (4): 245-50, 1972 Jul-Aug. [PUBMED Abstract]
13. Rosen GM, Shorr RI: Laetrile: end play around the FDA. A review of legal developments. Ann Intern Med 90 (3): 418-23, 1979. [PUBMED Abstract]
14. Curran WJ: Law-medicine notes. Laetrile for the terminally ill: Supreme Court stops the nonsense. N Engl J Med 302 (11): 619-21, 1980. [PUBMED Abstract]
15. Fenselau C, Pallante S, Batzinger RP, et al.: Mandelonitrile beta-glucuronide: synthesis and characterization. Science 198 (4317): 625-7, 1977. [PUBMED Abstract]
16. Chandler RF, Anderson LA, Phillipson JD: Laetrile in perspective. Can Pharm J 117 (11): 517-20, 1984.
17. Newmark J, Brady RO, Grimley PM, et al.: Amygdalin (Laetrile) and prunasin beta-glucosidases: distribution in germ-free rat and in human tumor tissue. Proc Natl Acad Sci U S A 78 (10): 6513-6, 1981. [PUBMED Abstract]
18. Rauws AG, Olling M, Timmerman A: The pharmacokinetics of prunasin, a metabolite of amygdalin. J Toxicol Clin Toxicol 19 (8): 851-6, 1982. [PUBMED Abstract]
19. Kochi M, Takeuchi S, Mizutani T, et al.: Antitumor activity of benzaldehyde. Cancer Treat Rep 64 (1): 21-3, 1980. [PUBMED Abstract]
20. Kochi M, Isono N, Niwayama M, et al.: Antitumor activity of a benzaldehyde derivative. Cancer Treat Rep 69 (5): 533-7, 1985. [PUBMED Abstract]
21. Gostomski FE: The effects of amygdalin on the Krebs-2 carcinoma and adult and fetal DUB(ICR) mice. [Abstract] Diss Abstr Int B 39 (5): 2075-B, 1978.
22. Herbert V: Laetrile: the cult of cyanide. Promoting poison for profit. Am J Clin Nutr 32 (5): 1121-58, 1979. [PUBMED Abstract]
23. Viehoever A, Mack H: Bio-chemistry of amygdalin (bitter, cyanogenetic principle from bitter almonds). Am J Pharm 107 (Oct): 397-450, 1935.

Amygdalin was first isolated in 1830 by two French chemists.[1,2] It was used as an anticancer agent in Russia as early as 1845, and positive results were reported for the first patient treated.[3,4] The first recorded use of amygdalin in the United States as a treatment for cancer occurred in the early 1920s.[5] At that time, amygdalin was taken in pill form; however, the formulation was judged too toxic, and the work was abandoned. In the 1950s, a purportedly nontoxic intravenous form of amygdalin was patented as Laetrile.[1,6,7]

Laetrile has been tested on cultured animal cells, in whole animals, in xenograft models, and in humans to determine whether it has specific anticancer properties. As noted in the General Information section, hydrogen cyanide is believed to be the main cancer-killing ingredient in laetrile.[8,9] When amygdalin interacts with the enzyme beta-glucosidase or undergoes hydrolysis in the absence of enzymes, hydrogen cyanide, benzaldehyde, and glucose are produced.[1,7,8,10,11] Hydrogen cyanide can also be produced from prunasin, which is a less-than-complete breakdown product of amygdalin.[1,8]

Proponents of laetrile have proposed four different theories to explain its purported anticancer activity. The first of these incorporates elements of the trophoblastic theory of cancer, a theory that is not widely accepted as an explanation for cancer formation. According to the trophoblastic theory, all cancers arise from primordial germ cells, some of which become dispersed throughout the body during embryonic development and, therefore, are not confined to the testes or ovaries.[12–17] The rationale for laetrile use is the suggestion that malignant cells have higher than normal levels of an enzyme called beta-glucuronidase (which is different from the enzyme beta-glucosidase) and that they are deficient in another enzyme called rhodanese (thiosulfate sulfurtransferase). Another suggestion is that laetrile is modified in the liver, and that beta-glucuronidase breaks down the modified compound, ultimately producing cyanide. Rhodanese can convert cyanide into the relatively harmless compound thiocyanate. Thus, it has been proposed that cancer cells are more susceptible to the toxic effects of laetrile than normal cells because of an imbalance in these two enzymes.[10,13,18–20] Some experimental evidence does support the idea that normal tissues and malignant tissues differ substantially in their concentrations of beta-glucuronidase [21] and rhodanese.[22,23]

The second theory states that cancer cells contain more beta-glucosidase activity than normal cells and, as in the first theory, that they are deficient in rhodanese.[1,5,13,15,18,24,25] Again, elevated beta-glucosidase activity in the interstitial regions of some malignancies has been experimentally demonstrated.[26,27]

The third theory states that cancer is the result of a metabolic disorder caused by a vitamin deficiency. It states further that laetrile, or amygdalin/vitamin B-17, is the missing vitamin needed by the body to restore health.[18,28–30] Experimental evidence indicates that the level of intake of individual vitamins and/or the vitamin status of an organism can influence the development of cancer, but there is no evidence that laetrile is needed for normal metabolism or that it can function as a vitamin in animals or humans.[31,32]

The fourth theory suggests that the cyanide released by laetrile has a toxic effect beyond its interference with oxygen utilization by cells. According to this theory, cyanide increases the acid content of tumors and leads to the destruction of lysosomes. The injured lysosomes release their contents, thereby killing the cancer cells and arresting tumor growth.[15] According to this theory, another consequence of lysosome disruption is stimulation of the immune system.

References

1. Dorr RT, Paxinos J: The current status of laetrile. Ann Intern Med 89 (3): 389-97, 1978. [PUBMED Abstract]
2. Viehoever A, Mack H: Bio-chemistry of amygdalin (bitter, cyanogenetic principle from bitter almonds). Am J Pharm 107 (Oct): 397-450, 1935.
3. The laetrile controversy. In: Moss RW: The Cancer Industry: The Classic Expose on the Cancer Establishment. First Equinox Press, 1996, pp 131-52.
4. Laetrile at Sloan-Kettering: a case study. In: Moss RW: The Cancer Industry: The Classic Expose on the Cancer Establishment. First Equinox Press, 1996, pp 153-86.
5. Curt GA: Unsound methods of cancer treatment. Princ Pract Oncol Updates 4 (12): 1-10, 1990.
6. Fenselau C, Pallante S, Batzinger RP, et al.: Mandelonitrile beta-glucuronide: synthesis and characterization. Science 198 (4317): 625-7, 1977. [PUBMED Abstract]
7. Chandler RF, Anderson LA, Phillipson JD: Laetrile in perspective. Can Pharm J 117 (11): 517-20, 1984.
8. Newmark J, Brady RO, Grimley PM, et al.: Amygdalin (Laetrile) and prunasin beta-glucosidases: distribution in germ-free rat and in human tumor tissue. Proc Natl Acad Sci U S A 78 (10): 6513-6, 1981. [PUBMED Abstract]
9. Rauws AG, Olling M, Timmerman A: The pharmacokinetics of prunasin, a metabolite of amygdalin. J Toxicol Clin Toxicol 19 (8): 851-6, 1982. [PUBMED Abstract]
10. Ross WE: Unconventional cancer therapy. Compr Ther 11 (9): 37-43, 1985. [PUBMED Abstract]
11. Ames MM, Moyer TP, Kovach JS, et al.: Pharmacology of amygdalin (laetrile) in cancer patients. Cancer Chemother Pharmacol 6 (1): 51-7, 1981. [PUBMED Abstract]
12. Krebs ET Jr, Krebs ET Sr, Beard HH: The unitarian or trophoblastic thesis of cancer. Med Rec 163 (7): 149-74, 1950.
13. Ellison NM: Unproven methods of cancer therapy. Drug Ther (NY) 10(July): 73-82, 1980.
14. Navarro MD: The Philippine experience in the early detection and chemotherapy of cancer. St Tomas J Med 25 (3): 125-33, 1970.
15. Greenberg DM: The case against laetrile: the fraudulent cancer remedy. Cancer 45 (4): 799-807, 1980. [PUBMED Abstract]
16. Levi L, French WN, Bickis IJ, et al.: Laetrile: a study of its physicochemical and biochemical properties. Can Med Assoc J 92 (20): 1057-61, 1965.
17. Treatment of cancer with laetriles; a report by the Cancer Commission of the California Medical Association. Calif Med 78 (4): 320-6, 1953. [PUBMED Abstract]
18. Unproven methods of cancer management. Laetrile. CA Cancer J Clin 22 (4): 245-50, 1972 Jul-Aug. [PUBMED Abstract]
19. Navarro MD: Five years experience with laetrile therapy in advanced cancer. Acta Unio Int Contr Cancrum 15(suppl 1): 209-21, 1959.
20. Morrone JA: Chemotherapy of inoperable cancer: preliminary report of 10 cases treated with laetrile. Exp Med Surg 20: 299-308, 1962.
21. Chen X, Wu B, Wang PG: Glucuronides in anti-cancer therapy. Curr Med Chem Anticancer Agents 3 (2): 139-50, 2003. [PUBMED Abstract]
22. GAL EM, FUNG FH, GREENBERG DM: Studies on the biological action of malononitriles. II. Distribution of rhodanese (transulfurase) in the tissues of normal and tumor-bearing animals and the effect of malononitriles thereon. Cancer Res 12 (8): 574-9, 1952. [PUBMED Abstract]
23. Sabelli R, Iorio E, De Martino A, et al.: Rhodanese-thioredoxin system and allyl sulfur compounds. FEBS J 275 (15): 3884-99, 2008. [PUBMED Abstract]
24. Herbert V: Laetrile: the cult of cyanide. Promoting poison for profit. Am J Clin Nutr 32 (5): 1121-58, 1979. [PUBMED Abstract]
25. Scott PJ: Laetrile and cancer quackery problems. Cancer Forum 5 (2): 93-97, 1981.
26. Cheng H, Cao X, Xian M, et al.: Synthesis and enzyme-specific activation of carbohydrate-geldanamycin conjugates with potent anticancer activity. J Med Chem 48 (2): 645-52, 2005. [PUBMED Abstract]
27. Bernacki RJ, Niedbala MJ, Korytnyk W: Glycosidases in cancer and invasion. Cancer Metastasis Rev 4 (1): 81-101, 1985. [PUBMED Abstract]
28. Lerner IJ: Laetrile: a lesson in cancer quackery. CA Cancer J Clin 31 (2): 91-5, 1981 Mar-Apr. [PUBMED Abstract]
29. Lerner IJ: The whys of cancer quackery. Cancer 53 (3 Suppl): 815-9, 1984. [PUBMED Abstract]
30. Shils ME, Hermann MG: Unproved dietary claims in the treatment of patients with cancer. Bull N Y Acad Med 58 (3): 323-40, 1982. [PUBMED Abstract]
31. Young VR, Newberne PM: Vitamins and cancer prevention: issues and dilemmas. Cancer 47 (5 Suppl): 1226-40, 1981. [PUBMED Abstract]
32. Jukes TH: Is laetrile a vitamin? Nutr Today 12 (5): 12-17, 1977.

Preclinical investigations of the potential anticancer activity of laetrile have used numerous cultured cell lines and tumor models, and they explored the following issues:

Animal studies of laetrile have used rodents,[1–10] dogs,[11–13] rabbits,[13] and a cat.[11] Early work led to the hypothesis that enzymes were necessary to release hydrogen cyanide from amygdalin. When high levels of these enzymes were present, symptoms of cyanide poisoning were more pronounced.[1,13]

In two studies sponsored by the National Cancer Institute and published in 1975, various rodent cancers (osteogenic sarcoma, melanoma, carcinosarcoma, lung carcinoma, and leukemia) were transplanted into rats and mice.[2,3] In both studies, the animals were treated with intraperitoneal injections of amygdalin, with or without the enzyme beta-glucosidase. None of the solid tumors or leukemias that were investigated responded to amygdalin at any dose that was tested. No statistically significant increase in animal survival was observed in any of the treatment groups. Similar results were obtained in another study using human breast cancer and colon cancer cells implanted into mice.[10] Amygdalin at every dose level tested produced no response either as a single agent or in combination with beta-glucosidase. It was discovered that animals experienced more side effects when beta-glucosidase was given concurrently with amygdalin than when amygdalin was given alone.[2,3]

Additional cell culture and animal studies involving more than a dozen other tumor models have been published.[1,4,6,8,9,14,15] In one study, preliminary findings by one of the principal investigators that amygdalin inhibited the growth of primary tumors and the incidence of lung metastases in mice bearing spontaneous (not treatment-induced) mammary adenocarcinomas could not be confirmed.[4] However, positive results were obtained in another study.[9] A summary of study results is provided in Table 1 and Table 2 below.

The toxicity of laetrile appears to be dependent on the route of administration. Oral administration is associated with much greater toxicity than intravenous, intraperitoneal, or intramuscular injection.[1,5,7,8,12,20–22] As noted in the History section, most mammalian cells contain only trace amounts of the enzyme beta-glucosidase;[23] however, this enzyme is present in gastrointestinal tract bacteria and in many food plants.[5,7,13,24–26]

Two studies have examined the role of intestinal bacteria in the breakdown of orally administered amygdalin.[7,27] In one study, rats bred and raised under germ-free conditions and rats bred and raised under normal conditions were given oral amygdalin. The germ-free rats exhibited no side effects from the compound, and their blood concentrations of cyanide were indistinguishable from those of untreated rats. Many of the rats with normal quantities of intestinal bacteria showed signs of cyanide poisoning (e.g., lethargy and convulsions), and they had high levels of cyanide in their blood. In the second study, rats were either treated or not treated with the antibiotic neomycin before being given oral amygdalin.[5] In this study, urinary excretion of detoxified cyanide (i.e., thiocyanate) was measured. The amount of urinary thiocyanate was 40 times higher in rats that had not been given the antibiotic, indicating that more amygdalin had been broken down in animals with normal amounts of intestinal bacteria. In humans, as in rats, substantial breakdown of amygdalin occurs in the intestines; however, little breakdown of amygdalin occurs in humans, with most of the intact compound eventually excreted in urine.[25,28]

References

1. Gostomski FE: The effects of amygdalin on the Krebs-2 carcinoma and adult and fetal DUB(ICR) mice. [Abstract] Diss Abstr Int B 39 (5): 2075-B, 1978.
2. Wodinsky I, Swiniarski JK: Antitumor activity of amygdalin MF (NSC-15780) as a single agent and with beta-glucosidase (NSC-128056) on a spectrum of transplantable rodent tumors. Cancer Chemother Rep 59 (5): 939-50, 1975 Sep-Oct. [PUBMED Abstract]
3. Laster WR, Schabel FM: Experimental studies of the antitumor activity of amygdalin MF (NSC-15780) alone and in combination with beta-glucosidase (NSC-128056). Cancer Chemother Rep 59 (5): 951-65, 1975 Sep-Oct. [PUBMED Abstract]
4. Stock CC, Tarnowski GS, Schmid FA, et al.: Antitumor tests of amygdalin in transplantable animal tumor systems. J Surg Oncol 10 (2): 81-8, 1978. [PUBMED Abstract]
5. Newton GW, Schmidt ES, Lewis JP, et al.: Amygdalin toxicity studies in rats predict chronic cyanide poisoning in humans. West J Med 134 (2): 97-103, 1981. [PUBMED Abstract]
6. Hill GJ, Shine TE, Hill HZ, et al.: Failure of amygdalin to arrest B16 melanoma and BW5147 AKR leukemia. Cancer Res 36 (6): 2102-7, 1976. [PUBMED Abstract]
7. Carter JH, McLafferty MA, Goldman P: Role of the gastrointestinal microflora in amygdalin (laetrile)-induced cyanide toxicity. Biochem Pharmacol 29 (3): 301-4, 1980. [PUBMED Abstract]
8. Khandekar JD, Edelman H: Studies of amygdalin (laetrile) toxicity in rodents. JAMA 242 (2): 169-71, 1979. [PUBMED Abstract]
9. Manner HW, DiSanti SJ, Maggio MI, et al.: Amygdalin, vitamin A and enzyme induced regression of murine mammary adenocarcinomas. J Manipulative Physiol Ther 1 (4): 246-8, 1978.
10. Ovejera AA, Houchens DP, Barker AD, et al.: Inactivity of DL-amygdalin against human breast and colon tumor xenografts in athymic (nude) mice. Cancer Treat Rep 62 (4): 576-8, 1978. [PUBMED Abstract]
11. Lewis JP: Laetrile. West J Med 127 (1): 55-62, 1977. [PUBMED Abstract]
12. Schmidt ES, Newton GW, Sanders SM, et al.: Laetrile toxicity studies in dogs. JAMA 239 (10): 943-7, 1978. [PUBMED Abstract]
13. Dorr RT, Paxinos J: The current status of laetrile. Ann Intern Med 89 (3): 389-97, 1978. [PUBMED Abstract]
14. Levi L, French WN, Bickis IJ, et al.: Laetrile: a study of its physicochemical and biochemical properties. Can Med Assoc J 92 (20): 1057-61, 1965.
15. Koeffler HP, Lowe L, Golde DW: Amygdalin (Laetrile): effect on clonogenic cells from human myeloid leukemia cell lines and normal human marrow. Cancer Treat Rep 64 (1): 105-9, 1980. [PUBMED Abstract]
16. Park HJ, Yoon SH, Han LS, et al.: Amygdalin inhibits genes related to cell cycle in SNU-C4 human colon cancer cells. World J Gastroenterol 11 (33): 5156-61, 2005. [PUBMED Abstract]
17. Chang HK, Shin MS, Yang HY, et al.: Amygdalin induces apoptosis through regulation of Bax and Bcl-2 expressions in human DU145 and LNCaP prostate cancer cells. Biol Pharm Bull 29 (8): 1597-602, 2006. [PUBMED Abstract]
18. Zhou C, Qian L, Ma H, et al.: Enhancement of amygdalin activated with β-D-glucosidase on HepG2 cells proliferation and apoptosis. Carbohydr Polym 90 (1): 516-23, 2012. [PUBMED Abstract]
19. Chen Y, Ma J, Wang F, et al.: Amygdalin induces apoptosis in human cervical cancer cell line HeLa cells. Immunopharmacol Immunotoxicol 35 (1): 43-51, 2013. [PUBMED Abstract]
20. Moertel CG, Ames MM, Kovach JS, et al.: A pharmacologic and toxicological study of amygdalin. JAMA 245 (6): 591-4, 1981. [PUBMED Abstract]
21. Newmark J, Brady RO, Grimley PM, et al.: Amygdalin (Laetrile) and prunasin beta-glucosidases: distribution in germ-free rat and in human tumor tissue. Proc Natl Acad Sci U S A 78 (10): 6513-6, 1981. [PUBMED Abstract]
22. Navarro MD: Five years experience with laetrile therapy in advanced cancer. Acta Unio Int Contr Cancrum 15(suppl 1): 209-21, 1959.
23. Conchie J, Findlay J, Levvy GA: Mammalian glycosidases: distribution in the body. Biochem J 71 (2): 318-25, 1959.
24. Herbert V: Laetrile: the cult of cyanide. Promoting poison for profit. Am J Clin Nutr 32 (5): 1121-58, 1979. [PUBMED Abstract]
25. Ames MM, Moyer TP, Kovach JS, et al.: Pharmacology of amygdalin (laetrile) in cancer patients. Cancer Chemother Pharmacol 6 (1): 51-7, 1981. [PUBMED Abstract]
26. Unproven methods of cancer management. Laetrile. CA Cancer J Clin 22 (4): 245-50, 1972 Jul-Aug. [PUBMED Abstract]
27. Shils ME, Hermann MG: Unproved dietary claims in the treatment of patients with cancer. Bull N Y Acad Med 58 (3): 323-40, 1982. [PUBMED Abstract]
28. Ames MM, Kovach JS, Flora KP: Initial pharmacologic studies of amygdalin (laetrile) in man. Res Commun Chem Pathol Pharmacol 22 (1): 175-85, 1978. [PUBMED Abstract]

Laetrile has been used as an anticancer treatment in humans worldwide.[1] Although many anecdotal reports and case reports are available, findings from only two clinical trials [2,3] have been published. No controlled clinical trial of laetrile has ever been conducted.

Case reports and reports of case series have provided little evidence to support laetrile as an anticancer treatment.[1,4–8] The absence of a uniform documentation of cancer diagnosis, the use of conventional therapies in combination with laetrile, and variations in the dose and duration of laetrile therapy complicate evaluation of the data. In a case series published in 1962,[6] findings from ten patients with various types of metastatic cancer were reported. These patients had been treated with a wide range of doses of intravenous (IV) Laetrile (total dose range, 9–133 g). Pain relief (reduction or elimination) was the primary benefit reported. Some objective responses, such as decreased adenopathy and decreased tumor size, were noted. Information on prior or concurrent therapy was provided; however, patients were not followed up long-term to determine whether the benefits continued after treatment was stopped. Another case series that was published in 1953 included 44 cancer patients and found no evidence of objective response that could be attributed to laetrile.[9] Most patients with reported cancer regression in this series received recent or concurrent radiation therapy or chemotherapy. Thus, it is impossible to determine which treatment produced the positive results.

Benzaldehyde, which is one of laetrile’s breakdown products, has also been tested for anticancer activity in humans. Two clinical series reported a number of responses to benzaldehyde in patients with advanced cancer for whom standard therapy had failed.[10,11] In one series, 19 complete responses and ten partial responses were reported among 57 patients who had received either oral or rectal beta-cyclodextrin benzaldehyde; however, precise response durations were specified for only two of the patients.[10] Another series by the same investigators used 4,6-benzylidene-alpha-D-glucose, which is an IV formulation of benzaldehyde.[11] In this series, seven complete responses and 29 partial responses were reported among 65 patients, with response durations ranging from 1.5 to 27 months. No toxicity was associated with either preparation of benzaldehyde, and it was reported that the responses persisted as long as treatment was continued. Almost all of the patients in these two series had been treated previously with chemotherapy or radiation therapy, but the elapsed time before the initiation of benzaldehyde treatment was not disclosed.

In 1978, the National Cancer Institute (NCI) requested case reports from practitioners who believed that their patients had benefitted from laetrile treatment.[12] Ninety-three cases were submitted, and 67 were considered evaluable for response. An expert panel concluded that two of the 67 patients had complete responses and that four of the others had partial responses while using laetrile.[13] On the basis of these six responses, the NCI agreed to sponsor phase I and phase II clinical trials.

The phase I study was designed to test the doses, routes of administration, and the schedule of administration judged representative of those used by laetrile practitioners.[3] The study involved six cancer patients. The investigators found that IV and oral amygdalin showed minimal toxicity under the conditions evaluated; however, two patients who ate raw almonds while undergoing oral treatment developed symptoms of cyanide poisoning.

The phase II study was conducted in 1982 and was designed to test the types of cancer that might benefit from laetrile treatment.[2] Most patients had breast, colon, or lung cancer. To be eligible for the trial, patients had to be in good general condition (not totally disabled or near death), and they must not have received any other cancer therapy for at least 1 month before treatment with amygdalin. Amygdalin, evaluated for potency and purity by the NCI,[14] was administered by IV for 21 days, followed by oral maintenance therapy, utilizing doses and procedures similar to those evaluated in the phase I study. Vitamins and pancreatic enzymes were also administered as part of a metabolic therapy program that included dietary changes to restrict the use of caffeine, sugar, meats, dairy products, eggs, and alcohol. A small subset of patients received higher-dose amygdalin therapy and higher doses of some vitamins as part of the trial. Patients were followed up until there was definite evidence of cancer progression, elevated blood cyanide levels, or severe clinical deterioration. Among 175 evaluable patients, only one patient met the criteria for response. This patient, who had gastric carcinoma with cervical lymph node metastasis, experienced a partial response that was maintained for 10 weeks while on amygdalin therapy. Fifty-four percent of the patients had measurable disease progression at the end of the IV course of treatment, and all of the patients had disease progression 7 months after completing IV therapy. Seven percent of the patients reported an improvement in performance status (ability to work or to perform routine daily activities) at some time during therapy, and 20 percent claimed symptomatic relief. In most patients, these benefits did not persist. Blood cyanide levels were not elevated after IV amygdalin treatment; however, they were elevated after oral therapy.[2]

Variations in commercial preparations of laetrile from Mexico, the primary supplier, have been documented.[14,15] Incorrect product labels have been found, and samples contaminated with bacteria and other substances have been identified.[14,15] When a comparison was made of products manufactured in the United States and Canada, differences in chemical composition were noted, and neither product was effective in killing cultured human cancer cells.[16]

References

1. Lewis JP: Laetrile. West J Med 127 (1): 55-62, 1977. [PUBMED Abstract]
2. Moertel CG, Fleming TR, Rubin J, et al.: A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N Engl J Med 306 (4): 201-6, 1982. [PUBMED Abstract]
3. Moertel CG, Ames MM, Kovach JS, et al.: A pharmacologic and toxicological study of amygdalin. JAMA 245 (6): 591-4, 1981. [PUBMED Abstract]
4. Navarro MD: The Philippine experience in the early detection and chemotherapy of cancer. St Tomas J Med 25 (3): 125-33, 1970.
5. Ross WE: Unconventional cancer therapy. Compr Ther 11 (9): 37-43, 1985. [PUBMED Abstract]
6. Navarro MD: Five years experience with laetrile therapy in advanced cancer. Acta Unio Int Contr Cancrum 15(suppl 1): 209-21, 1959.
7. Morrone JA: Chemotherapy of inoperable cancer: preliminary report of 10 cases treated with laetrile. Exp Med Surg 20: 299-308, 1962.
8. Brown WE, Wood CD, Smith AN: Sodium cyanide as a cancer chemotherapeutic agent: laboratory and clinical studies. Am J Obstet Gynecol 80 (5): 907-18, 1960.
9. Treatment of cancer with laetriles; a report by the Cancer Commission of the California Medical Association. Calif Med 78 (4): 320-6, 1953. [PUBMED Abstract]
10. Kochi M, Takeuchi S, Mizutani T, et al.: Antitumor activity of benzaldehyde. Cancer Treat Rep 64 (1): 21-3, 1980. [PUBMED Abstract]
11. Kochi M, Isono N, Niwayama M, et al.: Antitumor activity of a benzaldehyde derivative. Cancer Treat Rep 69 (5): 533-7, 1985. [PUBMED Abstract]
12. Newell GR, Ellison NM: Ethics and designs: laetrile trials as an example. Cancer Treat Rep 64 (2-3): 363-5, 1980 Feb-Mar. [PUBMED Abstract]
13. Ellison NM, Byar DP, Newell GR: Special report on Laetrile: the NCI Laetrile Review. Results of the National Cancer Institute’s retrospective Laetrile analysis. N Engl J Med 299 (10): 549-52, 1978. [PUBMED Abstract]
14. Davignon JP, Trissel LA, Kleinman LM: Pharmaceutical assessment of amygdalin (Laetrile) products. Cancer Treat Rep 62 (1): 99-104, 1978. [PUBMED Abstract]
15. Davignon JP: Contaminated laetrile: a health hazard. N Engl J Med 297 (24): 1355-6, 1977. [PUBMED Abstract]
16. Levi L, French WN, Bickis IJ, et al.: Laetrile: a study of its physicochemical and biochemical properties. Can Med Assoc J 92 (20): 1057-61, 1965.

The side effects associated with laetrile treatment mirror the symptoms of cyanide poisoning. Cyanide is a neurotoxin that can cause the following side effects:

Oral laetrile causes more severe side effects than injected laetrile. These side effects can be potentiated by the concurrent administration of raw almonds or crushed fruit pits, and by eating fruits or vegetables that contain beta-glucosidase (e.g., celery, peaches, bean sprouts, carrots),[3,5,14–16] or by taking high doses of vitamin C orally.[1,5,17,18]

References

1. Howard-Ruben J, Miller NJ: Unproven methods of cancer management. Part II: Current trends and implications for patient care. Oncol Nurs Forum 11 (1): 67-73, 1984 Jan-Feb. [PUBMED Abstract]
2. Moertel CG, Fleming TR, Rubin J, et al.: A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N Engl J Med 306 (4): 201-6, 1982. [PUBMED Abstract]
3. Chandler RF, Anderson LA, Phillipson JD: Laetrile in perspective. Can Pharm J 117 (11): 517-20, 1984.
4. Leor R, Michaeli J, Brezis M, et al.: Laetrile intoxication and hepatic necrosis: a possible association. South Med J 79 (2): 259-60, 1986. [PUBMED Abstract]
5. Lee M, Berger HW, Givre HL, et al.: Near fatal laetrile intoxication: complete recovery with supportive treatment. Mt Sinai J Med 49 (4): 305-7, 1982 Jul-Aug. [PUBMED Abstract]
6. Navarro MD: Five years experience with laetrile therapy in advanced cancer. Acta Unio Int Contr Cancrum 15(suppl 1): 209-21, 1959.
7. Dorr RT, Paxinos J: The current status of laetrile. Ann Intern Med 89 (3): 389-97, 1978. [PUBMED Abstract]
8. Smith FP, Butler TP, Cohan S, et al.: Laetrile toxicity: a report of two patients. Cancer Treat Rep 62 (1): 169-71, 1978. [PUBMED Abstract]
9. Vizel M, Oster MW: Ocular side effects of cancer chemotherapy. Cancer 49 (10): 1999-2002, 1982. [PUBMED Abstract]
10. Kalyanaraman UP, Kalyanaraman K, Cullinan SA, et al.: Neuromyopathy of cyanide intoxication due to “laetrile” (amygdalin). A clinicopathologic study. Cancer 51 (11): 2126-33, 1983. [PUBMED Abstract]
11. Ames MM, Moyer TP, Kovach JS, et al.: Pharmacology of amygdalin (laetrile) in cancer patients. Cancer Chemother Pharmacol 6 (1): 51-7, 1981. [PUBMED Abstract]
12. Moertel CG, Ames MM, Kovach JS, et al.: A pharmacologic and toxicological study of amygdalin. JAMA 245 (6): 591-4, 1981. [PUBMED Abstract]
13. O’Brien B, Quigg C, Leong T: Severe cyanide toxicity from ‘vitamin supplements’. Eur J Emerg Med 12 (5): 257-8, 2005. [PUBMED Abstract]
14. Gostomski FE: The effects of amygdalin on the Krebs-2 carcinoma and adult and fetal DUB(ICR) mice. [Abstract] Diss Abstr Int B 39 (5): 2075-B, 1978.
15. Schmidt ES, Newton GW, Sanders SM, et al.: Laetrile toxicity studies in dogs. JAMA 239 (10): 943-7, 1978. [PUBMED Abstract]
16. Herbert V: Laetrile: the cult of cyanide. Promoting poison for profit. Am J Clin Nutr 32 (5): 1121-58, 1979. [PUBMED Abstract]
17. Calabrese EJ: Conjoint use of laetrile and megadoses of ascorbic acid in cancer treatment: possible side effects. Med Hypotheses 5 (9): 995-7, 1979. [PUBMED Abstract]
18. Bromley J, Hughes BG, Leong DC, et al.: Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C. Ann Pharmacother 39 (9): 1566-9, 2005. [PUBMED Abstract]

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of the scores and additional information about levels of evidence analysis for cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

1. What is laetrile (amygdalin)?

   Laetrile is a compound that has been used as a treatment for people with cancer. Laetrile is another name for amygdalin. Amygdalin is a bitter substance found in fruit pits, such as apricots, raw nuts, lima beans, clover, and sorghum. It makes hydrogen cyanide which is changed into cyanide when taken into the body. Hydrogen cyanide is thought to kill cancer cells. Laetrile is also called Vitamin B-17, although it has not been approved as a vitamin by the American Institute of Nutrition Vitamins.

2. How is laetrile given?

   Laetrile is given by mouth (orally) as a pill. It can also be given by injection into a vein (IV) or muscle (intramuscular). Laetrile is commonly given by IV at first, then orally as maintenance therapy (treatment given to help extend the benefit of previous therapy).

   Laetrile treatments are given in Mexico and some U.S. clinics. Sometimes laetrile is given in combination with a metabolic therapy program (special diet, high-dose vitamins, and pancreatic enzymes).

3. Have any laboratory or animal studies been done using laetrile?

   In laboratory studies, tumor cells are used to test a substance to find out if it is likely to have any anticancer effects. In animal studies, tests are done to see if a drug, procedure, or treatment is safe and effective in animals. Laboratory and animal studies are done before a substance is tested in people.

   Laboratory and animal studies have tested the effects of laetrile in laboratory experiments. For information on laboratory and animal studies done using laetrile, see the Laboratory/Animal/Preclinical Studies section of the health professional version of Laetrile/Amygdalin.

4. Have any studies of laetrile been done in people?

   No controlled clinical trials of laetrile have been reported. Anecdotal reports and case reports have not shown laetrile to be an effective treatment for cancer.

   Benzaldehyde, which is made when laetrile is broken down by the body, has been tested for anticancer activity in people. In two clinical series, patients with advanced cancer who had not responded to standard therapy were treated with benzaldehyde. Some patients had a complete response, while some had a decrease in tumor size. The response to benzaldehyde only lasted during treatment. Most of the patients had been treated with chemotherapy or radiation therapy.

   The National Cancer Institute requested case reports from practitioners who believed their patients were helped by treatment with laetrile. An expert panel concluded that 2 of 67 patients had complete responses and 4 had a decrease in tumor size.

   Findings from 2 clinical trials conducted by the National Cancer Institute reported the following:

   • A phase I study tested doses, schedules, and ways to give amygdalin in 6 cancer patients. Researchers found that amygdalin caused very few side effects at the prescribed doses when given by mouth or by IV. Two patients who ate raw almonds while taking amygdalin had side effects.
   • A phase II study with 175 patients looked at what types of cancer might benefit from treatment with amygdalin. Most of the patients in this study had breast, colon, or lung cancer. In about half of the patients, cancer had grown by the end of the treatment. Cancer had grown in all patients 7 months after treatment ended. Patients reported improved symptoms, such as the ability to work or do other activities. These improvements did not last after treatment ended.
5. Have any side effects or risks been reported from laetrile?

   The side effects of laetrile treatment include the following:

   • Nausea and vomiting.
   • Headache.
   • Dizziness.
   • Blue color of the skin caused by a lack of oxygen in the blood.
   • Liver damage.
   • Very low blood pressure.
   • Droopy upper eyelid.
   • Trouble walking caused by damaged nerves.
   • Fever.
   • Confusion.
   • Coma.
   • Death.

   The side effects of laetrile depend on the way it is given. Side effects are worse when laetrile is given by mouth. While taking laetrile, side effects get worse when:

   • Eating raw almonds or crushed fruit pits.
   • Eating certain types of fruits and vegetables, such as celery, peaches, bean sprouts, and carrots.
   • Taking high doses of vitamin C.
6. Is laetrile approved by the FDA for use as a cancer treatment in the United States?

   The U.S. Food and Drug Administration (FDA) has not approved laetrile as a treatment for cancer or any other medical condition. Laetrile is made in Mexico. The way that laetrile is made is not regulated by the FDA, so batches of laetrile may vary in purity and contents.

Complementary and alternative medicine (CAM)—also called integrative medicine—includes a broad range of healing philosophies, approaches, and therapies. A therapy is generally called complementary when it is used in addition to conventional treatments; it is often called alternative when it is used instead of conventional treatment. (Conventional treatments are those that are widely accepted and practiced by the mainstream medical community.) Depending on how they are used, some therapies can be considered either complementary or alternative. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease.

Unlike conventional treatments for cancer, complementary and alternative therapies are often not covered by insurance companies. Patients should check with their insurance provider to find out about coverage for complementary and alternative therapies.

Cancer patients considering complementary and alternative therapies should discuss this decision with their doctor, nurse, or pharmacist as they would any type of treatment. Some complementary and alternative therapies may affect their standard treatment or may be harmful when used with conventional treatment.

It is important that the same scientific methods used to test conventional therapies are used to test CAM therapies. The National Cancer Institute and the National Center for Complementary and Integrative Health (NCCIH) are sponsoring a number of clinical trials (research studies) at medical centers to test CAM therapies for use in cancer.

Conventional approaches to cancer treatment have generally been studied for safety and effectiveness through a scientific process that includes clinical trials with large numbers of patients. Less is known about the safety and effectiveness of complementary and alternative methods. Few CAM therapies have been tested using demanding scientific methods. A small number of CAM therapies that were thought to be purely alternative approaches are now being used in cancer treatment—not as cures, but as complementary therapies that may help patients feel better and recover faster. One example is acupuncture. According to a panel of experts at a National Institutes of Health (NIH) meeting in November 1997, acupuncture has been found to help control nausea and vomiting caused by chemotherapy and pain related to surgery. However, some approaches, such as the use of laetrile, have been studied and found not to work and to possibly cause harm.

The NCI Best Case Series Program which was started in 1991, is one way CAM approaches that are being used in practice are being studied. The program is overseen by the NCI’s Office of Cancer Complementary and Alternative Medicine (OCCAM). Health care professionals who offer alternative cancer therapies submit their patients’ medical records and related materials to OCCAM. OCCAM carefully reviews these materials to see if any seem worth further research.

When considering complementary and alternative therapies, patients should ask their health care provider the following questions:

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) at the National Institutes of Health (NIH) facilitates research and evaluation of complementary and alternative practices, and provides information about a variety of approaches to health professionals and the public.

CAM on PubMed

NCCIH and the NIH National Library of Medicine (NLM) jointly developed CAM on PubMed, a free and easy-to-use search tool for finding CAM-related journal citations. As a subset of the NLM’s PubMed bibliographic database, CAM on PubMed features more than 230,000 references and abstracts for CAM-related articles from scientific journals. This database also provides links to the websites of over 1,800 journals, allowing users to view full-text articles. (A subscription or other fee may be required to access full-text articles.)

Office of Cancer Complementary and Alternative Medicine

The NCI Office of Cancer Complementary and Alternative Medicine (OCCAM) coordinates the activities of the NCI in the area of complementary and alternative medicine (CAM). OCCAM supports CAM cancer research and provides information about cancer-related CAM to health providers and the general public via the NCI website.

National Cancer Institute (NCI) Cancer Information Service

U.S. residents may call the Cancer Information Service (CIS), NCI’s contact center, toll free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 am to 9:00 pm. A trained Cancer Information Specialist is available to answer your questions.

Food and Drug Administration

The Food and Drug Administration (FDA) regulates drugs and medical devices to ensure that they are safe and effective.

Federal Trade Commission

The Federal Trade Commission (FTC) enforces consumer protection laws. Publications available from the FTC include: