Success Story

A computer-generated model of a Taxol molecule. Courtesy of NCI. 1991.

Taxol® (NSC 125973)

Taxol

Transcript

“The chemical structure of Taxol is unique and it looked extremely interesting to me, so I said yes, please send me 10 milligrams. Within a month we knew that we had a very interesting molecule that was doing something to cells, which no one else had seen occur with a small molecule. It was very exciting.”

— Susan Horwitz, Ph.D.¹

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