BATTLE WEARY

By STEVEN FOSTER

Cancer has become a powerful and foreboding enemy, requiring great strategy, bravery, and open-mindedness to hope to beat it. Years of searching for a cure have proven fruitless, although the efforts haven’t gone unrewarded. Surgery, radiotherapy, and chemotherapy have given us ways to stall the disease and, in some cases, force it into remission. Meanwhile, news of preventive measures and miracle cures provide us with both hope and confusion.

Herbal treatments are a part of this. In the coming months, Herbs for Health will occasionally explore herbal treatments in a series of articles about cancer—what research is being done, what research is showing. We also will attempt to set the record straight about the effectiveness and ineffectiveness of herbal remedies.We begin this series with an overview of plant-derived drugs currently used in the United States in chemotherapy.

IN BOTH conventional and alternative approaches to treating cancer, plants have played an important role. For more than thirty-five years, the National Cancer Institute (NCI) has been researching potential anticancer agents from plants. From 1960 to 1980, its researchers screened about 35,000 species of higher (flowering) plants for activity against cancer. About 3,000 of those demonstrated reproducible activity, and a small fraction of these were eventually chosen for clinical trials.

Mayapple

Long recognized as a medicinal plant, mayapple (Podophyllum peltatum) grows in damp woods from Quebec to Florida and west to Texas and Minnesota. In the last century, mayapple was widely used as a cleanser and to induce vomiting and expel parasites. Be forewarned that the root is highly toxic and may cause vomiting, diarrhea, headache, bloating, stupor, and/or lowered blood pressure.

While researching podophyllin resin obtained from mayapple rhizomes, Jonathan Hartwell, formerly head of NCI’s natural products branch, discovered clues that suggested may­apple as a possible anticancer agent. He found historical references to the use of mayapple against cancer in many cultures. For example, the Penobscot Indians of Maine used it. An 1849 American materia medica (a treatise on the sources, nature, properties, and preparation of drugs) recommended the resin as a treatment for cancerous tumors, polyps, and “unhealthy granulations”. Physicians in Mississippi used it as early as 1897, and in Louisiana it was a folk remedy for venereal warts.

Hartwell’s exhaustive survey of the historical and folk literature turned up anecdotal evidence of anticancer activity from more than 3,000 plant species. As a result of his efforts, mayapple is now used in conventional cancer treatment. Derivatives of podophyllotoxin, a compound found in the herb’s resin, are analogues for the production of two semisynthetic drugs, etoposide and teniposide, which are used in the treatment of testicular cancer and small-cell lung cancer.

Taxol

The pinnacle of NCI’s success in its natural-products screening program is paclitaxel (now better known by its trade name, Taxol), a chemotherapy drug derived from the bark of the Pacific yew (Taxus brevifolia) and the needles of other yew species. (The trade name Taxol is owned by Bristol-Myers Squibb Company, makers of the drug.)

The Pacific yew is a small evergreen tree found scattered throughout forests from southeastern Alaska to northern California and eastward to Montana and Idaho. It is rarely cultivated. Other species in the genus Taxus, including English yew (T. baccata) and Japanese yew (T. cuspidata), are widely grown as ornamentals. The foliage, bark, and seeds of yews are poisonous.

In 1962, the U.S. Department of Agriculture collected Pacific yew bark for NCI because paclitaxel, like many other compounds, had shown activity against several experimental leukemia cell models. In 1975, observation of strong activity in the B16 melanoma system created more interest in the compound. Further tests showed significant experimental activity in a number of human tumors, including one form of breast cancer. A breakthrough occurred in 1979 when researchers at the Albert Einstein Institute in New York discovered how the compound prevents the reproduction of cancer cells. By 1980, toxicological studies had begun, and formulation studies were completed.

In 1983, the U.S. Food and Drug Administration (FDA) granted approval for the first phase of clinical trials to study paclitaxel’s safety and evaluate doses and regimes. Progress was slow because of severe shortages in the supply of yew bark. (The Pacific yew is a slow-growing tree often found in old-growth forests, and harvesting the tree’s bark destroys it.) Preliminary reports showing a response rate of 30 percent in ovarian cancer studies exacerbated the supply problem by increasing the demand for Taxol for clinical trials. In 1991 and 1992, studies showed that patients with metastatic breast cancer (responsible for the death of 40,000 women per year in the United States) responded positively to the drug as did patients with advanced lung cancer, cancer of the head and neck, melanoma, and lymphomas.

In 1993, Taxol was approved as a therapeutic agent for ovarian cancer resistant to other treatments and in 1994, for certain forms of breast cancer.

The current FDA approval of Taxol for treatment of ovarian cancer applies only after other therapies have failed, but increasingly physicians are using it for first-line therapy. Some 55 percent of ovarian cancer patients in the United States are currently receiving Taxol as part of their primary therapy. In May 1995, a clinical study by William McGuire, of Emory University’s Cancer Center, reported that about 73 percent of nearly 400 women responded favorably to treatment with a combination of Taxol and another chemotherapy agent, cisplatin, and recommended that this combination become the standard of therapy worldwide for women with ovarian cancer.

Taxol is now being produced from the leaves of other yew species, collected in India and Europe, as well as from the bark of the Pacific yew. In its ­efforts to respond to the Taxol supply crisis, NCI learned an important lesson about the need for close communication between ­organiza­tions responsible for drug procurement and clinical investigators. In the future, NCI plans to initiate ­exploration into large scale-up of raw material production as soon as antitumor activity has been confirmed in a substance.

Madagascar periwinkle

Madagascar periwinkle (Catharanthus roseus, formerly Vinca rosea) has been a major source of chemotherapeutic agents for the past thirty years. Native to Madagascar, it is now a cosmopolitan weed in tropical regions and is widely grown as an attractive ornamental. In the early 1960s, researchers in Canada and the United States, working independently, became interested in the plant based on its folk use in diabetes. They discovered a large number of alkaloids that demonstrated anticancer activity in animal experiments. More than seventy different alkaloids, some of which are known to stop cell division in cancer cells, have since been isolated. Two of them, vinblastine and vincristine, were further developed as chemotherapy drugs and came into the market in the mid-1960s. In combination with other drugs, vinblastine is used to treat Hodgkin’s disease and other cancers. Vincristine is used to treat acute leukemia and, in combination with other drugs, Hodgkin’s disease and Wilms’ tumor. In 1984, a semisynthetic derivative of vinblastine, vindesine, became available for use in patients resistant to vincristine and vinblastine. The discovery of the two major anticancer alkaloids from the Madagascar periwinkle has sparked further research into plant-­derived cancer treatments.

The story of two folk remedies

Several other plant compounds are in clinical trials, and time will tell whether they will result in new drugs. Success in the NCI’s natural products branch has been slow in coming. With the advent of new technologies and collaboration with researchers through­out the world, the development of other plant-derived cancer drugs is probable. Because the search for new conventional cancer treatments is long and tedious, individuals diagnosed with cancer continue to seek out alternative therapies, with mixed results. The following are two examples of widely used folk cures whose reputation has not stood up in the laboratory.

Chaparral: The low-growing shrub known as chaparral or creosote bush (Larrea tridentata) is commonly found in the southwestern deserts of the United States and northern Mexico. Products made from chaparral leaves have been included in capsulated products, tinctures, and other forms for more than twenty years. During this period, people consumed hundreds of tons of chaparral with no known reports of toxicity until recently.

Chaparral first achieved its fame as a cancer folk remedy among Mormon populations in the Southwest. The claims of its effectiveness persuaded Tom Murdock, founder of one of the largest herb product companies in the United States—Murdock Madaus Schwabe, manufacturers of the Nature’s Way line—to turn to chaparral as a cancer treatment for his gravely ill wife, Lalovi. Conventional treatment had left the couple with little hope, but Murdock was determined not to sit idle. He found a chaparral bush, harvested some leaves, and prepared them for his wife; his wife recovered completely after the treatment and subsequently lived for more than twenty years. As news of the cure spread, Murdock, responding to the demand for chaparral products, in 1969 founded Nature’s Way Research Laboratories in Phoenix, Arizona, specifically to make and sell chaparral tablets.

At about the same time, researchers in Salt Lake City were ­designing a clinical study to test chaparral for antitumor activity after observing a patient who had experienced remission, attributed to the use of chaparral, of malignant mela­noma. The 1968–1969 clinical trial at the University of Utah included fifty-nine patients with advanced incurable malignant tumors of various origins. Of the patients who experienced side effects from the use of chaparral, thirteen reported nausea and vomiting; nine, diarrhea; two, ­abdominal cramps; and one, rash, stomatitis, and fever. Tests of liver function were normal. Until 1990, these were the main side effects reported from the use of chaparral.

The study did not definitively demonstrate anticancer activity in chaparral, however. The National Cancer Advisory Council’s standard for an effective anticancer agent is that it produce a significant regression (20 percent) of a specific cancer type for a minimum of two months. Although tumor regression was reported in a few of the patients, the ­results were inconclusive.

In 1990, a case of subacute liver disease attributed to chaparral in a thirty-three-year-old woman was reported. In December 1992, the FDA’s Center for Food Safety and Applied Nutrition issued a press release warning of the potential link between use of the herb and liver toxicity. In the same month, the American Herbal Products Association asked its members to suspend sales of chaparral in response to the agency’s action. Since then, a number of other cases of liver disease related to chaparral use have been reported. The mechanism of the toxicity problem has not yet been determined. It came as a surprise to many users that chaparral could produce toxic reactions; thousands of people have used capsulated products of the herb for years with no reports of side effects. The herb disappeared from store shelves at the time but is now quietly reappearing, mostly in combination products.

Essiac: It is impossible to explore the field of alternative cancer remedies without running into the word “Essiac”. Essiac is an herbal remedy said to have originated with the Indians of northern Ontario. In 1922, an elderly patient gave the formula to Renée Caisse, a nurse in an Ontario hospital. (Essiac is “Caisse” spelled backward.) In 1924, Caisse tried the formula on her mother, who had been diagnosed with inoperable liver cancer. After using the formula, Caisse’s mother was said to have lived for another eighteen years. Caisse then devoted her life to treating cancer patients with the formula free of charge. By 1938, with hundreds of testimonials to its healing powers, Caisse approached the Canadian parliament for recognition of the formula but was turned down. Caisse died at age ninety in 1978, having kept the formula a secret throughout her life.

Several persons have laid claim to ownership of the formula, reported to have been bequeathed to the Resperin Corporation and to David Fingard via Matthew Dymond, former deputy health minister of Ontario. Now the list of ingredients and various formulations for Essiac circulate widely in alternative cancer publications. The formula is prepared as a tea from various proportions of at least four (sometimes six) herbs, including Indian rhubarb (Rheum palmatum), sheep sorrel (Rumex acetosella), slippery elm (Ulmus rubra), and burdock root (Arctium lappa). The most potent herb, the strongly laxative Indian rhubarb, constitutes the smallest part of the formula.

Essiac is not approved by any authority for treatment of cancer. Attempts have been made by its advocates to have it accepted into clinical trials. In 1978, the Canadian government allowed Laval University and the Toronto General Hospital to investigate the formula in cancer patients. Family practitioners were allowed to supervise terminally ill cancer patients on an Essiac regime when no other treatment was possible. The formula was apparently of no benefit in the vast majority of these cases. Evaluation of the formula in NCI’s tumor screening systems also has produced no positive results.

Steven Foster, who lives and writes in Fayetteville, Arkansas, is a member of the Herbs for Health Editorial Advisory Board. This article is adapted from “Cancer and the Plant World” in The Herb Companion of August/September 1995.

Additional reading

Cragg, G. M., et al. Journal of Natural Products 1993, 56(10):1657–1668.
Duke, J. A. Foreward in J. L. Hartwell, Plants Used Against Cancer—A Survey. Lawrence, Kansas: Quarterman, 1982.
Foster, S. Forest Pharmacy. Durham, North Carolina: Forest History Society, 1995.
Hartwell, J. L. Cancer Treatment Report. 60(8):1031–1068.
Katz, M., and F. Saibil. Journal of Clinical Gastroenterology 1990, 12(2):203–206.
Smart, C. R., et al. Cancer Chemotherapy Report 1969, Part 1, 53:147.
Smart, C.R., et al. Rocky Mountain Medical Journal 1970:39–43.
Tyler, V. E., et al. Pharmacognosy, 9th ed. Philadelphia: Lea & Febiger, 1988.