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From the Townsend Letter
February/March 2007


War on Cancer:
Some Promising Non-Conventional Treatments
by Ralph W. Moss, PhD

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What are some of the best treatments that can be used by naturopathic doctors for the treatment of cancer? There are dozens, but in this article, I will discuss a number of the most promising: Avemar, cimetidine, maitake, melatonin, pau d'arco, and Sun soup.

Sold in the US under the brand name Avé, Avemar is a nutritional supplement manufactured from fermented wheat germ. Avemar helps regulate the processes of cellular metabolism and supports mechanisms of immune regulation. The active ingredients of Avemar are several ubiquinones – in particular, DMBQ (standardized 2-methoxy benzoquinone and 2,6 dimethoxybenzoquinone). There have been some formal clinical and laboratory investigations of Avemar, and the picture that emerges is a highly positive one. For instance, a study published in the Journal of Pediatric Hematology and Oncology found that fermented wheat germ could reduce chemotherapy-induced neutropenia in children undergoing treatment for various kinds of leukemia (Garami 2004).

Avemar also has supportive value in colorectal cancer (Jakab 2003). A Hungarian clinical trial showed that Avemar, when added to standard therapy for stage III colorectal cancer, had important adjunctive effects: 170 colorectal cancer patients received standard anticancer therapies. Of this group, 66 also received this fermented wheat germ extract. The new recurrence rate was just three percent in the Avemar group vs. 17.3% in the standard group. Similarly, the death rate was just 12.1% vs. 31.7% in the standard treatment group (Farkas 2005).

Cimetidine (Tagamet)
Cimetidine (Tagamet) is a readily available, over-the-counter ulcer and indigestion remedy that has demonstrated some surprising anticancer effects. Roswell Park Cancer Institute (Buffalo, New York) scientists have shown cimetidine to be a "potent immunomodulating agent" (Nakajima 1991) that reverses the decline in the cellular-mediated immunity often seen in cancer patients (Nishiguchi 2003).

The first positive report on cimetidine came from Dr. James O. Armitage, MD, past president of the American Society of Clinical Oncology (ASCO), at the University of Nebraska, Omaha. He gave cimetidine to two lung cancer patients, one of whom had brain metastases. Both patients experienced unanticipated remissions of their cancer (Armitage 1979). In 1982, late-stage cancer patients were given 1,000 mg per day of cimetidine for gastric distress. Several had rapid remissions of their cancer. Other late-stage cancer patients also had impressive remissions (Thornes 1982; Borgstrom 1982).

Cimetidine has also been shown to potentiate interferon therapy in advanced melanoma. Dr. Per Flodgren reported that while no objective tumor responses were recorded with interferon treatment alone, six patients had objective tumor regressions when cimetidine was added to their interferon treatment (Flodgren 1983 and 1985).

At the 1999 ASCO meeting, Japanese scientists reported on the use of cimetidine in stomach cancer. Sixteen patients with progressive gastric cancer with distant metastases, and nine patients whose gastric cancer had recurred after surgery underwent chemotherapy plus cimetidine. A complete response of metastatic lesions was found in five cases and a partial response in 16 cases. Although the number of cases was rather small, the combination was effective in 21 out of 25, or 84% (Watanabe 1999).

At the 2004 ASCO meeting, Japanese scientists reported on a randomized clinical trial in patients with advanced renal cell carcinoma with lung metastases. Seventy-one patients from 32 institutions were randomly assigned to get either interferon-alfa (IFN) or IFN plus cimetidine. Among 36 evaluable patients in the IFN-alone group, there was a response rate of 15.2 %. But of 35 patients in IFN-plus-cimetidine group, there was a response rate of 29.4 % (Kinouchi 2004).

The usual dose of cimetidine for indigestion is 200 milligrams per day; however, in cancer, the effective dose seems to be between 800 and 1,000 mg per day. Even so, the cost is low. Patients should take this only under a doctor's supervision since cimetidine, albeit over-the-counter in the US, is a powerful drug that can occasionally interact with other drugs. The most dangerous potential interaction is with the anticancer agent BCNU (BiCNU or carmustine), used primarily for brain cancer. It has been known for decades that cimetidine can increase BCNU's bone marrow toxicity and that this interaction could be life-threatening (Selker 1978). There are also potential interactions with the drugs warfarin (Coumadin) and theophylline, an ingredient in tea and coffee.

A useful Asian medicinal mushroom is Grifola frondosa, known in Japanese as maitake. There are 25 articles on maitake and cancer listed in PubMed, most from the laboratory of Hiroaki Nanba, PhD, of Kobe Pharmaceutical University, Japan. Dr. Nanba isolated the D-fraction beta-glucan from maitake. Maitake D-Fraction has been found to enhance both arms of the immune response in normal mice. Therefore, Nanba concludes, "its administration may enhance host defense against foreign pathogens and protect healthy individuals from infectious diseases" (Kodama 2004). In some experiments, maitake D-Fraction also appears to arrest the progression of cancer cells. It primarily exerts this effect through stimulation of natural killer (NK) cell activity (Kodama 2003). It appears to work well with chemotherapy (Nie 2006).

In one of the most positive experiments, metastases to the liver were reduced by 81.3% in mice taking the oral maitake and 91.3% in the mice given injections of the D-fraction. Cancer cells present in the blood and/or lymph were killed via immune mechanisms that had been activated by the mushroom (Nanba 1995). D-fraction has the added benefit that it can be delivered as drops placed under the tongue. It is thus suitable for patients whose advanced disease prevents them from eating solid foods or supplements, such as those patients with cachexia (wasting syndrome).

Melatonin, the main hormone responsible for regulating sleep, was first isolated and characterized in 1958. Although known primarily as a regulator of circadian rhythms, melatonin has also been shown to exert anticancer activity through five different mechanisms. These are: 1) an anti-proliferative effect on cancer cells; 2) stimulation of anticancer immunity; 3) changes in the expression of oncogenes; 4) its role as a powerful antioxidant; and 5) anti-angiogenic effects.

There are over 1,000 PubMed-listed articles on the topic of melatonin and cancer, of which 66 are clinical trials. Dr. Paolo Lissoni, of Monza, Italy, believes that under experimental conditions, a neuroendocrine disorder precedes the development of clinical cancer. Every condition that diminishes the healthy functioning of the pineal gland and its output of melatonin, he says, increases the risk of cancer. When asked about causes of this malfunction of the "master gland," and therefore of cancer itself, Dr. Lissoni has singled out electromagnetic field emissions, chronic emotional stress, and mental depression. Such malfunctions, he says, almost always have significance in regard to the development of cancer.

In 1992, Dr. Lissoni's group found that adding melatonin to chemotherapy in metastatic non-small cell lung cancer (NSCLC) treatment had a beneficial effect on survival. All the patients in question had declined after receiving first-line chemotherapy containing cisplatin. The study included 63 patients who were randomized to receive either melatonin or best supportive care (BSC) alone. Patients were given ten milligrams per day of melatonin. These patients were then followed for one year from the time of progression after chemotherapy and were compared to the control group, which was randomized to receive supportive care alone. The percentage of both stabilization of disease and survival at one year was significantly higher in patients treated with melatonin than in those treated only with supportive care. In addition, not only was no drug-related toxicity noted but, on the contrary, treated patients "showed a significant improvement in performance status."

Two years later, Lissoni's group published an article in which they showed that melatonin added to the standard immune stimulant interleukin 2 (IL-2) increased survival, even in cancers in which IL-2 was not conventionally thought to be effective. This study was carried out in patients who had either locally advanced or metastatic solid tumors. The study included 80 consecutive patients, who were randomized to receive either IL-2 alone subcutaneously or IL-2 plus 40 mg per day of melatonin.

A complete response was obtained in none of the patients receiving IL-2 alone but in three of the 41 patients treated with IL-2 plus melatonin. A partial response was achieved in only one out of 39 patients treated with IL-2 alone but in eight of the 41 patients treated with IL-2 plus melatonin. Thus, the overall objective response rate was ten times greater (26.8%) in the melatonin-added group than in the group that received just IL-2. Not surprisingly, this difference was statistically significant (Lissoni 1994).

Pau d'arco
Pau d'arco is an ancient South American folk remedy, derived from the inner bark of a trumpet-flowered cross vine, Tabebuia impetiginosa (Argentina) or Tabebuia heptaphylla (Brazil). These are both members of the Bignonia family, plants that are native to the Caribbean and Central and South America, but that are now grown in the southern US as well.

Pau d'arco is one folk remedy that seems to also have a rational basis. There are at least twelve aromatic compounds in pau d'arco, the best-known and studied of which is lapachol, which was isolated in the 1850s from the wood of a Brazilian tree. In the 1960s, this was found to inhibit the growth of the Walker 256 rat carcinoma cell line when given orally (Rao 1968).

As a result of this study, Jerome Block, MD, performed a clinical trial in which 19 patients with advanced nonleukemic tumors and two with chronic myelocytic leukemia in relapse were given lapachol, in doses ranging from 250 to 3,750 milligrams per day. All 21 patients had previously and unsuccessfully received a variety of other therapies. One patient with metastatic breast cancer was cured of a single hip tumor, but there was no change in her numerous other bony lesions. All other patients either remained clinically unimproved or experienced advancing disease. But this trial may have been too short in duration to show pau d'arco's true effects. Pau d'arco may well be beneficial to cancer patients when taken over a period of months. There is, to my knowledge, minimal toxicity when taken as directed on the package. Pau d'arco is inexpensive and widely available in most countries. Unfortunately, the potency and authenticity of most pau d'arco remains murky, as there is no organization that independently assays medicinal herbs for purity, potency, safety, or efficacy. ( has never, to my knowledge, done a review.) The safest bet would be to buy a reputable national brand.

Sun Soup
This dietary-herbal supplement is centered around shiitake mushrooms and contains other mushrooms, soy, and Asian herbs. Alexander S. Sun, PhD, was a biochemist from the University of California, Berkeley, who did research at Mt. Sinai Medical Center, New York, and Yale University. He also directed an independent research laboratory in Milford, Conn. (Dr. Sun died of a sudden heart attack in July 2006.)

In 1984, Sun's mother developed lung cancer, which had metastasized to the lymph nodes and adrenal glands. She had surgery and a form of chemotherapy, but because of the severity of her case, survival seemed most unlikely. Dr. Sun therefore searched out Chinese food substances that had been demonstrated in the laboratory to have anticancer effects. From this information, he devised an immune-stimulating "soup" for his mother. Within eight months, her lung cancer was in complete remission. Many years later, she was alive, well, and free of cancer.

Dr. Sun then began making the soup for others – at first for friends, then commercially. Anecdotally, some patients reported good results. It was also studied clinically in patients with advanced non-small cell lung cancer. Today, both frozen and freeze-dried soups are marketed in the US as dietary supplements. Daily doses were used in the clinical studies in patients with advanced non-small cell lung cancer.

The soup was tested in standard Balb/C mice and produced between 53% and 74% inhibition of tumor growth; one out of eight animals had a complete tumor regression (CAP-CAM 1999). The first clinical paper concerned stage IIB and IV non-small cell lung cancer patients treated with this vegetable product and conventional therapies. Sun's coworker, Dr. Tom M. Fasy, reported on 14 out of 18 patients who took the soup for two months or more. These patients lived longer than patients who received chemotherapy alone (Sun 2001).

A controlled trial was also undertaken at the University of Palacky, Czech Republic. The control group consisted of 13 stage III and IV advanced lung cancer patients who did not eat the soup. The performance status in the comparable treatment group improved significantly. Median survival in the control group was just four months vs. 15 months in the Sun soup treatment group. A group of five early-stage patients was also treated for up to 24 months and, during that time, none had a recurrence of their tumor (Sun 1999).

Armitage JO, Sidner RD. Antitumour effect of cimetidine.
Lancet. 1979;1:882-883.

Balassiano IT, de Paulo SA, Silva NH, et al. Demonstration of the lapachol as a potential drug for reducing cancer metastasis.
Oncol Rep. 2005;13:329-333.

Block JB, Serpick AA, Miller W, et al. Early clinical studies with lapachol (NSC-11905).
Cancer Chemother Rep 2. 1974;4:27-28.

Borgstrom S, von Eyben FE, Flodgren P, et al. Human leukocyte interferon and cimetidine for metastatic melanoma.
N Engl J Med. 1982;307:1080-1081.

CAP-CAM 1999: Reported at the Cancer Advisory Panel for Complementary and Alternative Medicine: Minutes of the First Meeting. July 8-9, 1999.

Farkas E. Fermented wheat germ extract in the supportive therapy of colorectal cancer.
Orv Hetil. 2005 Sep 11;146(37):1925-1931.

Flodgren P, Malmstrom P, Axelsson B, et al. Immune functions in melanoma patients during treatment with interferon [HuIFN-alpha (Le)] alone or in combination with cimetidine.
Anticancer Res. 1985;5:197-204.

Flodgren P, Borgstrom S, Jonsson PE, et al. Metastatic malignant melanoma: regression induced by combined treatment with interferon [HuIFN-alpha(Le)] and cimetidine.
Int J Cancer. 1983;32:657-665.

Garami M, Schuler D, Babosa M, et al. Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients.
J Pediatr Hematol Oncol. 2004, 10:631-635.

Jakab F, Shoenfeld Y, Balogh A, et al. A medical nutriment has supportive value in the treatment of colorectal cancer.
Br J Cancer. 2003;89:465-469.

Kinouchi T, Sakamoto J, Tsukamoto T, et al. Prospective randomized trial of natural interferon-alpha (IFN) versus IFN + cimetidine in advanced renal cell carcinoma with pulmonary metastasis.
Journal of Clinical Oncology 2004 ASCO Annual Meeting/ Proceedings. 2004;22:4676.

Kodama N, Murata Y, Nanba H. Administration of a polysaccharide from Grifola frondosa stimulates immune function of normal mice.
J Med Food. 2004;7:141-145.

Lissoni P. Is there a role for melatonin in supportive care?
Support Care Cancer. 2002;10:110-116.

Lissoni P, Barni S, Ardizzoia A, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced non-small cell lung cancer resistant to a first-line chemotherapy containing cisplatin.
Oncology. 1992;49:336-339.

Lissoni P, Barni S, Tancini G, et al. A randomised study with subcutaneous low-dose interleukin 2 alone vs. interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma.
Br J Cancer. 1994;69:196-199.

Nakajima I, Chu TM. Synergistic antitumor activity of interleukin-2 and cimetidine against syngeneic murine tumor.
Cancer Immunol Immunother. 1991;33:9-14.

Nanba H. Activity of maitake D-fraction to inhibit carcinogenesis and metastasis. Ann NY Acad Sci. 1995;768:243-245.

Nie X, Shi B, Ding Y, Tao W. Preparation of a chemically sulfated polysaccharide derived from Grifola frondosa and its potential biological activities.
Int J Biol Macromol. 2006 Nov 15;39(4-5):228-233.

Nishiguchi S, Tamori A, Shiomi S, et al. Cimetidine reduces impairment of cellular immunity after transcatheter arterial embolization in patients with hepatocellular carcinoma.
Hepatogastroenterology. 2003;50:460-462.

Rao K, McBride TJ, Oleson JJ. Recognition and evaluation lapachol as an antitumor agent.
Cancer Res. 1968;28:1952-1954.

Russell WL, Lopez LM. Cimetidine-induced mental status changes: Case report and literature review.
Am J Hosp Pharm. 1980;37:1667-1671.

Selker RG, Moore P, Lodolce D. Bone-marrow depression with cimetidine plus carmustine.
N Engl J Med. 1978;299:834.

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. 2001;39:85-95.

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. 1999;34:62-69.

Thornes RD, Lynch G, Sheehan MV. Cimetidine and coumarin therapy of melanoma.
Lancet. 1982;2:328.

Watanabe S, Izumi S, N Miyosi N, et al. Chemotherapy combined with cimetidine for recurring and progressive gastric cancer. 1999 ASCO Annual Meeting Abstract No.1167.

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