Prospecting Biology?
The cancer drug Taxol originally came from the bark and needles of yew trees.
Are researchers taking advantage of nature when it comes to hunting for new medicines? Public concern has been
raised about scientists scouring the world's tropical rainforests and coral reefs to look for potential natural chemicals
that may end up being useful drugs. While it is true that rainforests in particular are home to an extraordinarily rich
array of species of animals and plants, many life-saving medicines derived from natural products have been
discovered in temperate climates not much different from our kitchens and backyards.
Many wonder drugs have arisen from non-endangered species, such as the bark of the willow tree, which was the
original source of aspirin. The antibiotic penicillin, from an ordinary mold, is another example. Although scientists first
found the chemical that became the widely prescribed cancer drug Taxol® in the bark of an endangered species of
tree called the Pacific yew, researchers have since found a way to manufacture Taxol in the lab, starting with an
extract from pine needles of the much more abundant European yew. In many cases, chemists have also figured out
ways to make large quantities of rainforest- and reef-derived chemicals in the lab (see Ocean Medicines).
http://publications.nigms.nih.gov/medbydesign/chapter3.html#c2
Image below from: http://www.realmagick.com/pacific-yew-tree
Taxol® (NSC 125973)
Paclitaxel, the most well-known natural-source cancer drug in the United States, is derived from the bark of the
Pacific yew tree (Taxus brevifolia) and is used in the treatment of breast, lung, and ovarian cancer, as well as
Kaposi's sarcoma.
1962 Samples of the Pacific yew's bark were first collected in 1962 by researchers from the U.S. Department of
Agriculture (USDA) who were under contract to NCI to find natural products that might cure cancer. Two years
later, Dr. Monroe E. Wall, Dr. Mansukh Wani, and colleagues at the Research Triangle Institute's Natural Product
Laboratory in Research Triangle Park, NC, discovered that extracts from this bark contained cytotoxic activity. In
1965, additional samples of bark were collected and sent to Dr. Wall's group for identification and purification of
the extract's most active component. It took the researchers at the Research Triangle Institute several years to
isolate paclitaxel in its pure form, but once they did, NCI assigned the compound an NSC number and testing
began to identify paclitaxel's biological action.
1977 It was not until 1977, when NCI was able to confirm antitumor activity in the mouse melanoma B16 model,
that paclitaxel, also known by its trade name, Taxol, was selected as a candidate for clinical development. Activity
was also observed in animal models against MX-1 mammary, LX-1 lung, and CX-1 colon tumors.
Also during that year, Dr. Susan Horwitz, Albert Einstein College of Medicine of Yeshiva University, was given a
grant by NCI to study Taxol's mechanism of action. Dr. Horwitz proved to be a good candidate to study Taxol, in
part because of her interest in naturally occurring small molecules and their use in treating cancer. 1
Dr. Horwitz found that Taxol was able to bind to a cell's microtubule assembly and slow cell division and growth
by stabilizing the microtubules, preventing shrinkage and therefore blocking the segregation of the
chromosomes.2
Because of difficulties harvesting Taxol and because of the complexities involved in synthesizing the compound,
development toward the clinic was slow. The drug, however, showed effectiveness against mammary tumors and
ovarian cancer, pushing researchers to find a means of isolating large quantities for clinical use. The first
company to achieve large-scale production of Taxol was Polysciences, Inc. Clinical trials became possible when a
method was derived to extract a precursor of Taxol, 10-deacetyl-baccatin III, from the common yew Taxus
baccata (which many people have in their gardens). The precursor was then converted by chemical synthesis to
Taxol. Currently, a cell culture method developed by Phyton Catalytic is used by Bristol-Myers Squibb (BMS) to
produce the drug.3
Taxol posed other challenges, too. It was difficult to formulate into a delivery system acceptable for human use.
Initial activity was observed with bulk drug suspended in solution. Although Taxol was soluble in 75%
polyethylene glycol, repeated testing using this formula against both B16 and P388 tumors produced inferior
results. When the drug was formulated in an ethanol, cremophor, and saline solution (ratio 5:5:90) to a
concentration of 0.3 to 0.6 mg/mL, the intraperitoneal activity was preserved at the initial levels. Preclinical toxic
effects were most evident in tissues with a high cell turnover, such as hematopoietic, lymphatic, gastrointestinal,
and reproductive tissues.
1984 In 1984, NCI began phase I clinical trials of Taxol against a number of cancer types. Demand for Taxol
spiked in 1989 after investigators at Johns Hopkins reported that the drug produced partial or complete responses
in 30% of patients with advanced ovarian cancer.4
1992–present In December 1992, the FDA approved Taxol for the treatment for ovarian cancer. Researchers also
tested the effectiveness of Taxol as a treatment for advanced breast cancer. Subsequent clinical trials found that
the drug was effective against this disease, and, in 1994, the FDA approved Taxol for use against breast cancer. 4
Clinical trials to test Taxol against other types of cancer and in combination with other therapies are currently in
progress.
To date, Taxol is the best-selling cancer drug ever manufactured. Annual sales of the drug peaked in 2000,
reaching $1.6 billion.5
1
Kreeger KY. Discovering How Taxol Works. Bryn Mawr S&T July 2001.
2
Harvard Medical School. Cancer Researcher Susan Band Horwitz, PhD Wins Warren Alpert Foundation
Prize for Work Developing Taxol. Press Release.
3
American Society of Pharmacognosy. The Story of Taxol.
4
University of Maryland Medical Center. About Taxol.
5
Wikipedia. Paclitaxel.
http://dtp.nci.nih.gov/timeline/flash/success_stories/S2_taxol.htm