Learn More About Paclitaxel

Overview
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it 'taxol'. When it was developed commercially by Bristol-Myers Squibb (BMS) the generic name was changed to 'paclitaxel' and the BMS compound is sold under the trademark 'Taxol'. In this formulation paclitaxel is dissolved in Cremophor EL, a polyoxyethylated castrol oil, as a delivery agent since paclitaxel is not soluble in water. A newer formulation, in which paclitaxel is bound to albumin as the delivery agent (Protein-bound paclitaxel), is sold commercially by Abraxis BioScience under the trademark Abraxane.[2]

Paclitaxel is now used to treat patients with lung, ovarian, breast cancer, head and neck cancer, and advanced forms of Kaposi's sarcoma. Paclitaxel is also used for the prevention of restenosis.

Paclitaxel works by interfering with normal microtubule growth during cell division. Together with docetaxel, it forms the drug category of the taxanes. It was the subject of a notable total synthesis by Robert A. Holton.

As well as offering substantial improvement in patient care, paclitaxel has been a relatively controversial drug. There was originally concern because of the environmental impact of its original sourcing, no longer used, from the Pacific yew. The assignment of rights, and even the name itself, to BMS were the subject of public debate and Congressional hearings.

How it works
Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules, 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 β subunit of tubulin. Tubulin is the "building block" of microtubules, and the binding of paclitaxel locks these building blocks 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 mechanism to transport other cellular components. For example, during mitosis, microtubules position the chromosomes during their replication and subsequent separation into the two daughter-cell nuclei.[35]

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.

In addition to stabilizing microtubules paclitaxel may act as a molecular mop by sequestering free tubulin effectively depleting the cells supply of tubulin monomers and/or dimers. This activity may trigger the aforementioned apoptosis.[36]

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.

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