Taxol

Paclitaxel is a drug used in the treatment of cancer. It was discovered at Research Triangle Institute (RTI) in 1967 when Dr. Monroe E. Wall and Dr. Mansukh C. Wani isolated the compound from the bark of the Pacific yew tree, Taxus brevifolia, and noted its antitumor activity in a broad range of rodent tumors. By 1970, the two scientists had determined the structure of paclitaxel, which is extremely complex. Paclitaxel has since become an effective tool of doctors who treat patients with ovarian and breast cancer and Kaposi's sarcoma. It is sold under the tradename Taxol®. Together with docetaxel, it forms the drug category of the taxanes.

Production

Unfortunately, the Pacific Yew is one of the slowest growing trees in the world. Further, the treatment of just one patient requires the cutting down and processing of six 100-year old trees. This supply problem combined with the threat to the endangered spotted owl (Strix occidentalis) has prompted researchers to develop a bacterium (Streptomyces coelicolor) that fermentatively produces a paclitaxel-like compound, as well as to examine the possibility of extracting paclitaxel-like compounds from the tree's needles instead of its bark.

Method of action

Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the tubulin protein of microtubules and locks them in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.

One common characteristic of most cancer cells is their rapid rate of cell division. In order to accommodate this, the cytoskeleton of a cell undergoes extensive restructuring. Paclitaxel is an effective treatment for aggressive cancers because it adversely affects the process of cell division by preventing this restructuring. Cancer cells are also destroyed by the aforementioned anti-Bcl-2 mechanism. Other cells are also affected adversely, but since cancer cells divide much faster than non-cancerous cells, they are far more susceptible to paclitaxel treatment.

Marketing

The license to commercialize and market Taxol is held by the Bristol-Myers Squibb Co., which was selected for this role by the U.S. National Cancer Institute. Bristol-Myers holds an exclusive contract in the harvesting of yew trees from US government lands; it has been criticized for having a "cancer monopoly" (Palast p.64).

ABI-007

In January 2005 the FDA approved Abraxane® (ABI-007) for clinical trials. In this preparation, paclitaxel is bonded to albumin as the delivery agent as an alternative to solvent (often toxic) delivery. [1]. The manufacturer heralds the drug as a breakthrough in nanotechnology [2].

References

• Greg Palast. The Best Democracy Money Can Buy. 2002.
• Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 1971;93:2325-7. PMID 5553076.

External links

• Molecule of the Month: TAXOL by Neil Edwards, University of Bristol.
• A Tale of Taxol from Florida State University.