The development of the chemotherapeutic cancer drug, Taxol, was designated an "emergency priority" in the early 1990s by the National Cancer Institute (NCI). Taxol was identified as one of the most promising anti-cancer drugs to be discovered in 20 years.
According to the American Cancer Society, ovarian cancer afflicted an estimated 24,000 American women during 1992, and 13,600 died. A women's lifetime risk for ovarian cancer was one in 65. Breast cancer was diagnosed in approximately 182,000 women during 1994, and 46,000 died. A woman's lifetime risk was one in nine.
After more than three decades of research and development (see "History of the Development of Taxol as a Cancer-Fighting Drug" on page 11), the Food and Drug Administration (FDA) finally approved Taxol for treatment of ovarian cancer on December 29, 1992, and for treatment of breast cancer on April 15, 1994. Unfortunately, the drug was not found to be effective against most cancers that more typically afflict men.
NCI began the search for a chemotherapeutic cancer drug in 1958 with a general plant species screening program. Extracts from more than 35,000 species were collected for anti-cancer testing. The Pacific yew tree (Taxus brevifolia Nutt.) was the first plant species to demonstrate anti-cancer properties. These properties were isolated in very low concentrations from extracts found in the bark of the Pacific yew.
Taxus brevifolia is a species of the genus Taxus (commonly named yew). The common name for this species is the Pacific yew. These trees are often found to be 200 years old in their native habitat.
As Taxol showed more and more promise during its early development, research personnel recognized that harvesting trees for bark would not provide a renewable source of this natural product. Whole trees had to be sacrificed. On average, three to four 150- to 200-year-old trees would have to be harvested to supply the necessary raw material (bark) to treat one cancer patient. An adequate supply of the drug could not be assured. The only place on the earth where the Pacific yew grew naturally was in forests in the northwestern United States, primarily in Oregon and Washington. Moreover, many citizens of the United States and other countries were opposed to the harvest of naturally occurring trees and shrubs because of perceived insults to a stable environment. In addition, this forested area was a natural home for the endangered, northern-spotted owl.
Other species of yews are commonly used in ornamental landscaping around our homes and public buildings. Major ones are Taxus baccata and Taxus cuspidata. A hybrid, Taxus x media, has also been designated an ornamental yew. While this hybrid cannot be verified, it is reported as Taxus cuspidata x Taxus baccata. More than 100 cultivars have been selected from these two species and this hybrid for landscape use. These yews have been used extensively in Eastern and Midwestern landscapes, especially since the turn of the century. Since they naturally mature to a medium- or large-sized shrub and are frequently used as small foundation plants in the landscape, they are regularly pruned to keep the planting in scale with the foundation area.
During the process of growing Taxus for landscape use, production nurseries annually prune Taxus plants to develop the small, dense, compact plant that is desired in the landscape marketplace. The clippings from these pruning operations fall to the ground and eventually break down and decompose. Dr. Edward M. Croom Jr., University of Mississippi, posed the following question: "Could these so-called waste clippings be collected after pruning and provide an annual renewable source of biomass for Taxol production?" Since only clippings were needed, whole plants would not have to be sacrificed.
For ornamental yews, the needles were found to be the primary source of Taxol, whereas the bark was the primary source from the Pacific yew. In addition, while the bark of the tree was found to have a Taxol content of approximately 0.01%, the needles of a popular ornamental hybrid yew, Taxus x media 'Hicksii,' were found to have more than 0.02%. Harvesting clippings offered the opportunity for a renewable Taxol source and associated economic benefits to nursery growers.
In the spring of 1991, the National Cancer Institute announced that a supply crisis for Taxol existed. There simply was not enough bark available to meet the demand for Taxol for clinical studies, let alone the anticipated demand if the drug were to be approved for general use. The question was raised: "Do we need to sacrifice a unique Pacific yew ecosystem in order to treat ovarian and breast cancer for our mothers, sisters, and daughters?"
Through funding from the NCI and the U.S. Department of Agriculture's Agricultural Research Service (USDA/ARS), a research team from the Ohio Agricultural Research and Development Center (OARDC) at The Ohio State University was asked to join the Research Institute of Pharmaceutical Sciences at the University of Mississippi and Zelenka Nursery, Inc., at Grand Haven, Michigan (the nation's largest producer of ornamental Taxus plants for landscapes), to form what was called the "Alliance for Taxol."
In response to the Taxol supply crisis, the Alliance for Taxol agreed to sign a contract to harvest, dry, store, and ultimately deliver 100,000 lbs. of Taxus clippings (wet-weight) to the National Cancer Institute by the summer of 1992. Approximately 25 research people from the three institutions contributed in one way or another to the work of the alliance. The contract was fulfilled.
A key to OARDC's participation in the alliance was the potential for inter-disciplinary research among departments at the research center and the years of Taxus research that had been conducted as a result of the Taxus collection at the Chadwick Living Herbarium of Taxus at OARDC's Secrest Arboretum. More than 100 types of Taxus plants were prophetically collected and planted, beginning in May 1942, by Dr. L. C. Chadwick and his graduate student, Raymond A. Keen. Fifty years later, as a part of the alliance's research efforts during 1991 and 1992, many samples of plant material were supplied to numerous research organizations worldwide that were involved in the search for the "super" Taxus cultivar that would ultimately yield maximum quantities of Taxol.
Fortunately, the Taxol supply crisis was at least temporarily eased by January 1994. Through a production process known as semi-synthesis, a precursor to Taxol, 10-deacetylbaccatin III, was successfully used to produce Taxol, which by then was generically identified as paclitaxel. Taxol was registered as the trade name for the formulated drug. The primary source of the taxane, 10-deacetylbaccatin III, was found from renewable biomass (twigs and needles) from the European yew (Taxus baccata) and the Himalayan yew (Taxus wallichiana). Unfortunately, as the names suggest, this material grows in Europe and Asia. Therefore, the urgent need for a renewable source of Taxus biomass from Ohio nurseries and those in surrounding states did not materialize.
The papers contained in this publication resulted from the valiant efforts of the 25 research people who responded to the urgent call for delivery of Taxus biomass for clinical studies of Taxol treatments for ovarian and breast cancer patients during the spring of 1991. Three of the papers were published in refereed scientific journals; two were presented as papers at annual meetings of the American Society of Agricultural Engineers; and four were progress reports that outlined work that was initiated but never finished because research funding ceased as fast as it began. The final paper in this document was presented as a summary of the work of the Alliance for Taxol at the National Cancer Institute's Workshop on Taxus, Taxol, and Taxotere in September of 1992.
This special circular, representing a compilation of the reports resulting from the work of the Alliance for Taxol, benefited immensely from the editing skills of Joy Ann Fischer from the Section of Communications and Technology.
Robert C. Hansen
Taxol is used in this special circular to refer to the drug that now has the generic name paclitaxel and the registered trade name Taxol® (Bristol-Myers Squibb Company, New York, N. Y.).
Taxotere is used in this publication to refer to the drug that now has the generic name docetaxel and the registered trade name Taxotere® (Rhone-Poulenc-Rorer Pharmaceuticals, Inc., Collegeville, Pa.).