THE MOSS REPORTS

This week I conclude a two-part discussion of the re-emergence of chaparral, an herbal treatment for cancer which was once considered by mainstream medicine to be nothing but a cruel and dangerous fraud. Now, a derivative of chaparral, M4N, is being tested in clinical trials for the treatment of head and neck cancer, a type of cancer that is notoriously resistant to standard therapies.

In more than thirty years of studying and chronicling developments in the field of cancer therapy I have seen many useful alternative treatments at first mercilessly vilified and driven underground, only to resurface years later when science eventually confirms that the active principle of such a treatment really does have some recognizable, quantifiable effect against cancer cells.

The fruit of my long career in this field is The Moss Reports, a comprehensive library of guides to both the conventional and alternative treatment of over 230 different kinds of cancer. For cancer patients there can be few more useful guides and decision-making tools than a Moss Report.

To order a Moss Report please visit our website, www.cancerdecisions.com, or call Diane at 1-800-980-1234 (814-238-3367 from outside the US).

We look forward to helping you.

HERB-DERIVED DRUG FIGHTS HEAD-AND-NECK CANCER, PART TWO

Contesting Claims

Scientific interest in chaparral surged in the late 1960s after an 85-year-old man came to the University of Utah with a proven malignant melanoma of the right cheek. He underwent four operations for this deadly form of skin cancer, but a tumor reappeared after each operation, and eventually the cancer spread to his neck. By the time he saw Dr. Charles Smart at the University of Utah, the lesion measured 3 by 4 centimeters (nearly 2 inches across).

In light of the poor results from the previous operations, the patient decided to avoid further surgery and returned home. He began taking chaparral tea in November 1967, and by February 1968 his facial lesion had decreased to the size of a dime, and the neck mass had also disappeared. In September 1968 he returned to be examined, and by that time the lesion had shrunk to a tiny 2-3 millimeters, and there were no masses in his neck. He looked much better and had gained twenty-five pounds. Even the American Cancer Society conceded that he had "marked regression of the cancer" (ACS 1971).

Based on this remarkable case, Dr. Smart and colleagues then carried out a study with fifty-nine cancer patients who took chaparral tea. Of these, forty-five completed the study, and four showed significant tumor regressions. Of the patients who responded with tumor regression, two had malignant melanoma, one had choriocarcinoma that had spread to the lungs, and one had widespread lymphoma. One of the melanoma patients experienced a 95 percent regression, whereupon the remaining growth was removed by surgical excision (Smart 1970).

Two other patients also had striking regression of their cancers, but were not included in the final tally. However, some patients paradoxically showed an apparent increase in tumor activity. This may be because at low doses chaparral or NDGA is said to stimulate tumor growth. It is only at higher dose levels that it begins to produce tumor regression (Pelton 1994)

A scientific article by Drs. Dean Burk and Mark Woods of the National Cancer Institute called NDGA "the penicillin of quinones," because the compound has a wide range of anticancer properties and is relatively nontoxic. They concluded that laboratory tests had shown that NDGA was one of the most potent cancer-killing anti-metabolites, in spite of what they judged to be its relatively low toxicity (Burk 1963).

Chaparral tea was subsequently investigated by scientists at other medical centers, including by the chairman of the biochemistry department at the University of Nevada. An Arizona scientist received an $81,000 contract to investigate treatments which might be developed from desert plants, and doctors in Reno began to use chaparral tea on their cancer patients.

In 1971, while research was still underway, the ACS placed chaparral tea on its unproven methods lists - a harsh blow at the time for any further investigations. In their statement of the time, the ACS wrote:

"After careful study of the literature and other information available to it, the American Cancer Society does not have evidence that treatment with chaparral tea results in objective benefit in the treatment of cancer in human beings" (ACS 1971:55).

This did not stop many people from trying to use the herb for cancers of every type. Alarmed over the growing popularity of the herb, and much later over several reports of liver damage following its use, the Food and Drug Administration (FDA) negotiated with food supplement manufacturers in 1992 to persuade them to not sell the product. Rather than face an outright ban, most of them readily complied.

The FDA website currently states:

"Chaparral, commonly called the creosote bush, is a desert shrub with a long history of use as a traditional medicine by Native Americans. Chaparral is marketed as a tea, as well as in tablet, capsule, and concentrated extract form, and has been promoted as a natural antioxidant ‘blood purifier,' cancer cure, and acne treatment.

"At least six cases (five in the United States and one in Canada) of acute non-viral hepatitis...have been associated with the consumption of chaparral as a dietary supplement. Additional cases have been reported and are under investigation. In the majority of the cases reported thus far, the injury to the liver resolves over time, after discontinuation of the product. In at least two patients, however, there is evidence that chaparral consumption caused irreversible liver damage. One patient suffered terminal liver failure requiring liver transplant.

"Most of these cases are associated with the consumption of single ingredient chaparral capsules or tablets; however, a few of the more recent cases appear to be associated with consumption of multi-ingredient products (capsules, tablets or teas) that contain chaparral as one ingredient. Chemical analyses have identified no contaminants in the products associated with the cases of hepatitis. Products from at least four different distributors and from at least two different sources have been implicated thus far."

The present-day ACS statement also focuses on the toxicity of the herb: "Chaparral is considered a dangerous herb that can cause irreversible, life-threatening liver damage. The FDA has cautioned against the internal use of chaparral. Research has not found it to be an effective treatment for cancer or any other disease. A study of nordihydroguaiaretic acid (NDGA), one of the chemicals in chaparral, concluded that it was not useful in treating people with cancer. Researchers continue to study NDGA in laboratory experiments."

This seems to be a remarkably one-sided evaluation of the available data on chaparral's effects on cancer. For example, no reference is given for the "study" in question, and one wonders what research it is based on. Most of the in vitro and in vivo studies cited in a comprehensive 2004 Institute of Medicine monograph are more positive than negative in nature, at least in regard to potential efficacy (Committee 2004). The only clinical trial mentioned by the IOM is the aforementioned 1970 study by Dr. Smart.

In addition, PubMed (the National Library of Medicine's comprehensive database of medical and scientific literature) also does not contain any negative clinical trials of chaparral or NDGA among its 15 million articles. To characterize chaparral as "not useful" seems tendentious. In fact, it is sad to see the modern-day ACS reverting to its ‘imaginative' negative evaluations of the past (such as I analyzed in detail in my book, The Cancer Industry).

But just how toxic is chaparral?

It is universally assumed that the use of chaparral constitutes a potential threat to the liver. The first report I know of detailing liver toxicity dates from the early 1980s. This concerned a woman who used tablets of chaparral leaf to treat a benign breast lump. She took 15 tablets per day, beginning in April 1983. By July she experienced nausea, loss of appetite, and gastric pain. By August she reduced the number of tablets to one per day, which cleared up her abdominal symptoms. She then once again increased the dosage to 7 per day, and experienced more severe problems. At this point she checked into a hospital and was found to be suffering from liver damage. A biopsy showed a 60-percent loss of essential liver cells. Fortunately, she recovered fully from the liver damage, and was discharged.

There are other cases as well. A review article by FDA scientists stated that eighteen cases of adverse events associated with the ingestion of chaparral had been reported to the FDA between 1992 and 1994. "There was evidence of hepatotoxicity [liver damage, ed.] in 13 [of these, ed.] cases....Jaundice with a marked increase in serum liver chemistry values, occurred 3 to 52 weeks after the ingestion of chaparral, and it resolved 1 to 17 weeks after most individuals stopped their intake of chaparral....[I]n 4 individuals, there was progression to cirrhosis; and in 2 individuals, there was acute fulminant liver failure that required liver transplants" (Sheikh 1997).

An even more alarming report came from surgeons at the Oregon Health and Science University in Portland, OR, in 2003. They stated that ten out of twenty of the liver transplant patients there who presented with fulminant hepatic failure [FHF – a particularly sudden and catastrophic form of liver failure, ed.] were recent or active users of potentially hepatotoxic supplements, including chaparral. The surgeons strongly urged enhanced public awareness of the danger of these supplements and an "increased regulatory oversight of their use" (Estes 2003).

However, a small study in the Journal of Alternative and Complementary Medicine raises some questions about the frequency of this type of adverse reaction. Two naturopaths in Sedona, Arizona followed four patients who were receiving low-dose chaparral for 22 months. The patients had complete blood counts and full blood chemistry panels both before and after treatment. According to the authors there was no indication of liver damage from use of Larrea [i.e., chaparral] even though one of these patients was already taking medications with a significant potential for hepatotoxicity.

"No patient in the study, whether using Larrea for short term or long, internally or externally, showed any sign of organ damage during the period of follow-up," the authors wrote. They concluded that "relatively small intakes of Larrea tincture, or topical application of extracts in Ricinus oil, are safe when prescribed by a clinically trained botanical prescriber."

However, they agreed that "Larrea should be used with caution in persons with a history of previous, or current, liver disease. It may be preferable to avoid the use of Larrea capsules because they have been associated with potentially dangerous overdosing" (Heron 2001).

Extract Vs. Herb

The debate concerning the use of whole herbs vs. using purified constituents is a very old one, which effectively split herbalists in the 19th century (see my book, Herbs Against Cancer). NDGA is only one of the many chemicals in chaparral. According to Dr. James Duke's US Department of Agriculture ethnobotanical database, there are at least a dozen others, some of which have been shown to have anticancer activity (USDA 2004). A 2001 study from the University of Buenos Aires, Argentina, showed that a water extract of chaparral (L. divaricata) had a much greater ability to kill lymphoma cells than did NDGA alone. The extract killed cancer cells in at least three separate ways: by increasing cAMP levels, by inhibiting protein kinase C (PKC) activity, and by influencing cellular calcium influx.

By comparison, NDGA alone failed to influence two out of three of those mechanisms. NDGA could only work, the researchers surmised, by inhibiting PKC. In addition, the amount of NDGA detected in the water extract was insufficient to account for the plant extract's anticancer activity. Although it is possible that NDGA "could have an additive effect on the activity of other compounds" (Anesini 2001), using NDGA as a stand-in for chaparral (and then declaring the herb itself ineffective) is a sleight-of-hand that most people can quickly see through.

This PubMed listed reference also challenges the idea that chaparral's anticancer activity is solely due to its best known component, NDGA. It does not take a conspiracy theorist to see that an unpatentable herb that sells for under $10 per pound does not have the same economic attractiveness as a purified, modified, synthesized drug that could eventually earn investors billions of dollars in returns.

Recommendations

I am excited by the revival of chaparral, in any form, as a cancer treatment. It is a bittersweet development, however, since the herb and its derivatives should have been more carefully tested back in the 1960s and 1970s, the way that NCI biochemist, Dean Burk, PhD, then urged. But does this mean that readers should rush out to take this herb?

Some readers, impatient with the slow pace of medical research and eager to find a cure for medical conditions for which no conventional treatment has proven effective, might be tempted to self-medicate with chaparral. Let me therefore make my position clear:

I STRONGLY DISCOURAGE ANYONE FROM USING CHAPARRAL AS A SELF-HELP TREATMENT AT THE PRESENT TIME.

That is because, despite the herb's great promise, the possibility of liver damage or other serious toxicity is simply too great to be ignored. In fact, I would go further. While I generally respect the judgment of most qualified herbalists, I would not take this herb even if it were recommended by an herbal practitioner. Its toxicity profile is just too uncertain to run the risk of serious harm to the liver.

On the other hand, I strongly urge further research not only on NDGA and M4N, but also on extracts of the whole chaparral plant. A concerted effort to explore the effects of the whole herb and its extracts, with informed consent and proper institutional review board approval and oversight, should be strongly supported and encouraged.

I will admit to mixed feelings about M4N. Of course, I certainly welcome any new anticancer drug and am excited by the two Phase I clinical studies that have been reported in 2004. But I would also like to see the whole chaparral plant investigated as a cancer treatment, picking up where Drs. Charles Smart, Dean Burk and others left off over three decades ago. Such a study could be very illuminating. However, any clinical study of the herb would of course have to include meticulous liver function monitoring to make sure that no hepatic damage is taking place.

But even these preliminary results with M4N go a long way towards vindicating the use of one of Native America's oldest alternative cancer treatments. Once again, the wisdom of folk medicine shines through.

References:

Anyone seriously interested in pursuing research into chaparral should consult the excellent 78-page booklet on the topic from the Institute of Medicine:

Committee on the Framework for Evaluating the Safety of Dietary Supplements. Food and Nutrition Board, Board on Life Sciences, US Institute of Medicine, Prototype Monograph on Chaparral (2004). Retrieved August 19, 2004 from:
http:// www.iom.edu/includes/DBFile.asp?id=19556

ACS (American Cancer Society). Unproven methods of cancer treatment: chaparral tea. New York, NY: American Cancer Society, 1970.

Anesini C, Genaro A, Cremaschi G, et al. "In vivo" and "in vitro" antitumoral action of Larrea divaricata. Physiol Pharmacol Ther Latinoam 1996;46:33-40.

Anesini C, Genaro A, Cremaschi G, Sterin Borda L, Borda E. Antimitogenic effect of Larrea divaricata Cav.: participation in arachidonate metabolism. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1999;46:245-52.

Anesini C, Turner S, Borda E, Ferraro G, Coussio J. Effect of Larrea divaricata Cav. extract and nordihydroguaiaretic acid upon peroxidase secretion in rat submandibular glands. Pharmacol Res 2004;49:441-448.

Burk D, Woods M. Hydrogen peroxide, catalase, glutathione peroxidase, quinones, NDGA, and phosphopyridine nucleotides in relation to X-ray action on cancer cells. Rad Res Suppl 1963;3:212–246.

Chen H, Teng L, Li J-H, Tseng WN, Mold DE, Huang RC. Antiviral activities of methylated nordihydroguaiaretic acids (II) Targeting herpes simplex virus replication by mutation insensitive transcription inhibitor tetra-O-methyl NDGA. J. Medicinal Chem 1998;41:3001-3007.

Craigo J, Callahan M, Huang RC, Delucia AL. Inhibition of human papilloma virus type 16 gene expression by nordihydroguaiaretic acid plant lignan derivatives. Antiviral Res 2000;47:19-28.

Dunphy FR, Dukelow KK, Provenzal J, Crawford J. Phase I clinical results of intralesional injection of tetra-o-methy nordihydroguaiaretic acid (M4N) in refractory head and neck cancer. ASCO Annual Meeting. Abstract No: 5614. Retrieved on August 20, 2004 from:
http://asco.org/ac/1,1003,_12-002644,00.asp

Estes JD, Stolpman D, Olyaei A, et al. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003;138:852-858.

Gisvold et al., Lignans from Larrea divaricata. J Pharmaceut Sci 1974;63:1905-1907.

Gnabre JN, Huang RC, Burns JJ, et al., Characterization of anti-HIV lignans from Larrea tridentata. Tetrahedron 1995:51:12203-12210.

Gnabre JN, Bates RB, Caldera S, Huang RC. Chemical structure of HIV-inhibitory lignans from Larrea tridentata. Tetrahedron 1995;51:12203-12210.

Gnabre JN, Brady J, Clanton D, et al. Inhibition of human immunodeficiency virus type 1 transcription and replication by DNA sequence-selective plant lignans. Proc Natl Acad Sci USA 1995;92:11239-11243.

Gnabre JN, Ito Y, Ma Y, Huang RC. Isolation of anti-HIV-1 lignans from Larrea tridentata counter-current Chromatography, Journal of Chromatography A 1996;719:353-364.

Heller JD, Kuo J, Wu TC, Kast WM, Huang RCC. Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells. Cancer Res 2001;61;5499-5504.

Heron S, Yarnell E. The safety of low-dose Larrea tridentata (DC) Coville (creosote bush or chaparral): a retrospective clinical study. J Altern Complement Med 2001;7:175-85.

Huang RCC, Li Y, Giza PE, et al. Novel antiviral agent tetraglycylated nordihydroguaiaretic acid hydrochloride as a host-dependent viral inhibitor. Antiviral Res. 2003;58:57-64.

Hwu JR, Tseng WN, Gnabre J, Giza P, Huang RC. Antiviral activities of methylated nordihydroguaiaretic acids. 1. Synthesis, structure identification, and inhibition of tat-regulated HIV transactivation. J Med Chem 1998;41:2994-3000.

Newall, C; Anderson, L; Phillipson, J. Herbal Medicines: A Guide for Healthcare Professionals. London: Pharmaceutical Press, 1996.

Park R, Giza PE, Mold DE, Huang RCC. Inhibition of HSV-1 replication and reactivation by the mutation-insensitive transcription inhibitor tetra-O-glycyl-nordihydroguaiaretic acid. Antiviral Res 2003;58, 35-45.

Pelton, Ross and Overholser, Lee. Alternatives in Cancer Therapy. New York: Fireside, 1994.

Perry CW, Kalniss, MV, Deitcher, KH. Synthesis of Lignans. I. Nordihydroguaiaretic Acid. Suppl.1. J Org Chem 1972;37:4371-4376.

Reuters News Service. Desert Shrub May Help Some Cancer Patients - Study, August 10, 2004. Retrieved August 19, 2004 from:
http://www.reuters.co.uk/newsArticle.jhtml?type=healthNews&storyID=5928053&section=news

Sheikh NM, Philen RM, Love LA. Chaparral-associated hepatotoxicity. Arch Intern Med 1997;157:913-919.

Smart CR, Hogle HH, Vogel H, Broom AD, Bartholomew D. Clinical experience with nordihydroguaiaretic acid--"Chaparrel tea" in the treatment of cancer. Rocky Mt Med J 1970;67:39–43.

United States Department of Agriculture (USDA). Dr. Duke's Phytochemical and Ethnobotanical Databases. Retrieved August 20, 2004 from:
http://www.ars-grin.gov/duke/

Zamora JM. Cytotoxic, Antimicrobial and Phytochemical Properties of Larrea Tridentata Cav. Auburn, AL: Auburn University. Dissertation, 1984.

Resources:

BioCure Medical LLC
940 Main Campus Dr., Suite 170
Raleigh, NC 27606
Phone: (919) 821-5204
Fax: (919) 821-5309
http://www.erimos.com/
James Oliver, PharmD (919-833-7196)
joliver@biocuretech.us

Clinical Trial:
Medical University of South Carolina (MUSC)
Charleston, SC 29475
Terry Day, MD, Principal Investigator
Betsy Sass, RN: 843-792-6325
sasse@musc.edu

Terry A. Day, MD
Head and Neck Surgery (ENT)
MUSC Medical Center
135 Rutledge Ave., Suite 1130
PO Box 250550
Charleston, SC 29425
1-800-424-MUSC (843-792-1414 in the Charleston area)
Email Address: dayt@musc.edu

Miscellaneous links:

Johns Hopkins' statement on Indian clinical trial:
http://www.jhu.edu/news_info/news/home01/jul01/india.html

Huge demonstrations in India:
http://www.flonnet.com/fl1817/18170110.htm

BioCure Medical study of M4N:
http://www.clinicaltrials.gov/ct/show/NCT00057512?order=1

Author of the ASCO paper:
Frank Dunphy, MD
DUMC 3685
Durham, NC 27710
Phone: (919) 684-5621
Fax: (919) 681-5864

Ru Chih Huang, PhD
Department of Biology
Johns Hopkins University
Phone: (410) 516-5181
Fax: (410) 516-5213
Email: rhuang@jhu.edu or huang@jhunix.hcf.jhu.edu.

IMPORTANT DISCLAIMER

The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.

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