Paclitaxel

Paclitaxel (Taxol) is a potent anti-neoplastic and anti-mitotic taxane drug used in cancer chemotherapy. Paclitaxel binds to the N-terminus of β-tubulin and and stabilizes microtubules arresting the cell cycle at the G2/M phase. The microtubule damage induces apoptosis through a JNK-dependent pathway followed by a JNK-independent pathway, perhaps related to the activation of protein kinase A (PKA) or of Raf-1 kinase, resulting in phosphorylation of Bcl-2. Paclitaxel stabilizes microtubules and as a result, interferes with the normal breakdown of microtubules during cell division. The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics, but recent studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At the higher therapeutic concentrations, paclitaxel appears to suppress microtubule detachment from centrosomes, a process normally activated during mitosis. The binding site for paclitaxel has been identified on the beta-tubulin subunit. In vitro and in vivo studies have demonstrated that paclitaxel is extensively metabolised by the liver to 3 primary metabolites.