When Paclitaxel, a drug found to have cancer-fighting properties, was extracted from Pacific yew trees, efforts to procure the drug raised questions of human welfare versus environmental depletion.

Humans have utilized the physiological activity of natural medicinals to treat pain and illness since ancient times. In 1960, the National Cancer Institute National Cancer Institute, U.S. (NCI) created a program to screen plant and animal species for chemicals (natural products) that might have anticancer properties. The scientists extracted compounds from natural tissues, which they tested for activity against laboratory cancer cells and mouse tumors. Between 1960 and 1981, the NCI tested extracts from 114,045 plant substances and 16,196 substances from animal sources. Of the 130,241 samples tested, only one compound, paclitaxel, demonstrated significant anticancer potential. Paclitaxel
Cancer;treatment
Yew trees
Pacific yew trees
Taxol
[kw]Paclitaxel Is Extracted from Pacific Yew Trees (1971)
[kw]Pacific Yew Trees, Paclitaxel Is Extracted from (1971)
[kw]Yew Trees, Paclitaxel Is Extracted from Pacific (1971)
[kw]Trees, Paclitaxel Is Extracted from Pacific Yew (1971)
Paclitaxel
Cancer;treatment
Yew trees
Pacific yew trees
Taxol
[g]North America;1971: Paclitaxel Is Extracted from Pacific Yew Trees[00110]
[g]United States;1971: Paclitaxel Is Extracted from Pacific Yew Trees[00110]
[c]Environmental issues;1971: Paclitaxel Is Extracted from Pacific Yew Trees[00110]
[c]Health and medicine;1971: Paclitaxel Is Extracted from Pacific Yew Trees[00110]
Holton, Robert
Horowitz, Susan
McGuire, William
Wall, Monroe

During 1962, the U.S. Forest Service Forest Service, U.S. collected plant samples from the forests of the Pacific Northwest. Among these samples were the bark, twigs, needles, and berries of the Pacific yew tree, Taxus brevifolia, a very slow-growing, understory resident of the coastal old-growth forests extending from southern Alaska to central California. Populations also exist in the Rocky Mountain region extending from southeastern British Columbia to central Idaho. At the NCI, a yew-bark extract showed activity against laboratory (9KB) cancer cells. This material was sent to Monroe Wall at the Research Triangle Institute in North Carolina. Wall had previously discovered a substance in the rosy periwinkle having both 9KB and mouse leukemia activity that was subsequently developed into a treatment for Hodgkin’s disease. He found that yew-bark extract was effective in trials against both the 9KB cell cultures and live-mouse leukemia. These results showed such promise that, in 1965, Wall began the arduous process of isolating the bark extract’s active ingredient.

In 1971, Wall’s group determined the structure of the active ingredient that became known as paclitaxel. Although Wall believed that paclitaxel had great potential, the NCI was not particularly interested in it because the compound was hard to work with and difficult to obtain. In order for the NCI to commit to the development of any anticancer drug, the drug had to do more than kill cancer cells in a test tube, a property demonstrated by many compounds. To be a target for development, the compound had to demonstrate superior potency, exhibit lower toxicity, or destroy the cancer cells in a novel manner. Throughout the early 1970’s, paclitaxel was only one of many chemicals that had shown some promise as an anticancer agent.

In the mid-1970’s, scientists developed a strain of mice having no immune system with which to reject foreign tissue, in hopes that human cancer cells implanted into these mice could be used for drug evaluation. In a feasibility study, implanted tumors were treated with a number of the NCI’s warehoused anticancer compounds. Paclitaxel was one of the test compounds. When paclitaxel was found to attack an implanted human cancer cell more effectively than any previously known compound, it became a target for development.

In 1978, Susan Horowitz, a molecular pharmacologist at the Albert Einstein College of Medicine in New York, along with a graduate student, Peter Schiff, Schiff, Peter began to study the mechanism by which paclitaxel destroyed cancer cells. They found that the paclitaxel paralyzed the cancer cells during their reproduction by interfering with the movement of fibers called microtubules. In preparation for cell division, cells form and organize microtubules into a particular framework that must be dismantled as the cells divide. Although a number of compounds were known to prevent cell division by interfering with the formation of microtubules, paclitaxel prevented cell division by stimulating the formation of such a stable framework that it could not be dismantled. It was this new mode of anticancer activity that motivated the NCI to schedule paclitaxel for clinical testing.

In 1983, phase 1 clinical trials, utilizing patients with advanced cancers that had not responded to other therapies, were carried out to determine what dosages of the drug could be administered to humans without killing them. After these toxicity and dosage data were collected, paclitaxel progressed to phase 2 clinical trials to determine if it would actually kill cancer cells in humans. In 1988, William McGuire and Eric Rowinsky Rowinsky, Eric of The Johns Hopkins University treated forty women with advanced cases of ovarian cancer that had proved unresponsive to traditional therapies with paclitaxel. Of these subjects, 30 percent experienced tumor shrinkage during treatment. This positive result led to tests on other types of cancers. In another study, breast cancer tumor shrinkage was observed in 48 percent of those undergoing the treatment. As a result of these preliminary findings, paclitaxel began to take on the proportions of a miracle drug.

Until the discovery of paclitaxel’s effectiveness in shrinking tumors, Pacific yew wood was considered to be of no value except as fence-post material and was traditionally left behind to rot as waste in clear-cut forests. Throughout the clinical testing period, the NCI directed the collection of yew bark and manufacture of paclitaxel. Although very little bark had been collected and only small quantities of paclitaxel produced, as the clinical trials expanded, the NCI became concerned about the ability to obtain sufficient quantities of paclitaxel for future use.

Pacific yew bark is peeled to extract paclitaxel, a drug found to have anticancer properties.

(National Cancer Institute)

There was some concern that if paclitaxel proved as effective as initial trials indicated, the yew population might become endangered by the demand for the drug. Conservationists contended that widespread harvesting of the tree would alter the old-growth forest Old-growth forests[Old growth forests] habitat that served as a home for many rare plants and animals. They argued that thousands of plant species had already become extinct because of careless deforestation and that other rare plants having therapeutic value could be destroyed. Indeed, because the Pacific yew takes ten to fifteen years to grow one inch in diameter and so many trees would be required to procure the cancer-fighting compound—one gram of paclitaxel is obtained from thirty pounds of harvested bark—commercial harvesting became a conservation issue. It seemed that a choice needed to be made between old-growth forest preservation and the potential saving of human lives.

Because paclitaxel production involved stripping the bark of the tree (thereby killing it) to isolate minute quantities of the drug, considerable interest was generated in developing new routes for obtaining the drug from the yew as well as devising methods to synthesize the drug in the laboratory. The first complete laboratory synthesis of paclitaxel was reported by Robert Holton of Florida State University in February, 1994.

More efficient methods of harvesting the native yew were instituted in an effort to save the trees. The bark must be left intact either on one side of the tree to allow for regeneration or at the bottom of the trunk to allow sprouting near the base, allowing the tree to survive. Samples from individual yew trees have been studied to identify any plants producing unusually large amounts of paclitaxel so that these plants can be used to propagate seedlings for use in nurseries and in reforestation of harvested areas. It is estimated that older yew harvesting practices wasted as much as half of the paclitaxel produced by the tree, because the needles and heartwood left to rot in the forest also contain the drug.

In the early 1990’s, the American pharmaceutical company Bristol-Myers Squibb Bristol-Myers Squibb[Bristol Myers Squibb] (BMS) obtained the exclusive rights to harvest, produce, test, and market paclitaxel, sold under the trade name Taxol. Conservationist critics argued that such a monopoly would remove the incentive for the company to be efficient in harvesting the trees and extracting the chemical from the bark. This agreement quickly gained many proponents in the Pacific Northwest region, where environmental constraints on old-growth logging had severely depressed the local timber-based economy.

In 1992, both the U.S. Food and Drug Administration and the Canadian Department of Health and Welfare approved paclitaxel for the treatment of ovarian cancer. Although many researchers still believed it to be the best new anticancer drug to be developed in many years, it was no longer being touted as a miracle drug because no patients had been cured of their cancers by paclitaxel. Although tumors were decreased in size, none was totally destroyed, and the shrunken tumors eventually regained their size, making paclitaxel a life-extending drug rather than a cancer-curing one.

Paclitaxel may be the most visible example of a molecule found in nature that can have a positive impact on human life. The success of paclitaxel increased curiosity in natural-product prospecting. It is estimated that less than 1 percent of the world’s naturally occurring species have been examined for potentially beneficial molecules, and many species are lost each year to urbanization and agricultural development. The reduction of the tropical rain forests Rain forests is of particular concern because these areas have an enormous concentration and diversity of species. The Natural Products Branch of the NCI has collected more than tens of thousands of samples of naturally occurring species, including a large number of tropical trees that, like the yew, are considered “trash” trees.

Costa Rica has has been a leader in natural-product prospecting by setting aside a quarter of its land for conservation purposes and establishing the Instituto Nacional de Biodiversidad to explore and index the region’s biodiversity, and allowing the pharmaceutical industry the right to develop any natural products discovered. This model program allows for the tapping of natural resources that can serve humanity while simultaneously conserving priceless ecosystems. Paclitaxel
Cancer;treatment
Yew trees
Pacific yew trees
Taxol

• Bylinsky, Gene. “The Race for a Rare Cancer Drug.” Fortune, July 13, 1992, 100-102. A discussion of research efforts aimed at increasing paclitaxel production. A sidebar shows how paclitaxel stops cancer cells from reproducing.
• Douglas, Daly. “Tree of Life.” Audubon 94 (March/April, 1992): 76-85. Discusses the history and environmental issues associated with paclitaxel.
• Erickson, Deborah. “Secret Garden.” Scientific American 265 (October, 1991): 121-122. A discussion of the potential use of biotechnology in paclitaxel production.
• Goodman, Jordan, and Vivien Walsh. The Story of Taxol: Nature and Politics in the Pursuit of an Anti-cancer Drug. New York: Cambridge University Press, 2001. Discusses the battle of interests between environmentalists fighting to protect the Pacific yew, the pharmaceutical companies who wished to procure paclitaxel, and the government agencies who stood in the middle.
• Joyce, Christopher. “Taxol: Search for a Cancer Drug.” BioScience 43 (March, 1993): 133-136. This article covers developments intended to alleviate conservation concerns associated with paclitaxel production. A sidebar chronicles the history of paclitaxel use.
• Junod, Tom. “Tree of Hope.” Life 15 (May, 1992): 71-76. A chronicle of the history of paclitaxel. Includes the story of the treatment of an ovarian cancer patient.

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