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.
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.
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.
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.
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.
