Taxane Therapy

Paclitaxel, a plant product from Taxus brevifolia, is an anticancer drug. Its mechanism of action is different from other cytotoxic agents. Paclitaxel enhances microtubule assembly. Paclitaxel is salvage therapy for patients with advanced ovarian cancer and metastatic breast cancer who have no response to prior chemotherapy with standard agents.

Paclitaxel, the first organic compound with a taxane ring, which has been shown antitumor activity, was isolated in 1967 from the bark of Pacific yew, Taxus brevifolia. Its mechanism of action is unique among antineoplastic agents. Paclitaxel promotes the assembly and stabilization of microtubules, which are intracellular structures essential for mitosis and other essential cellular functions. Unlike other antimicrotubule useful clinical agents such as vinca alkaloids and colchicine, which induce net disassembly by microtubules, paclitaxel changes the equilibrium toward microtubule assembly. The binding site of paclitaxel on microtubules also appears to be distinct from other antimicrotubule agents. It binds preferentially to the beta subunit of the microtubule, rather than tubulin dimmer. Paclitaxel induces several unique morphological effects on intracellular microtubules, including microtubule binding occurs during all phases of the cell cycle and mitotic asters of many anomalies.

Two mechanisms of acquired resistance to taxanes have been characterized. Cell lines lacking strength in their normal microtubule spindle and an inherently slow rate of microtubule Assembly when grown in the absence of drugs and require the continued presence of taxanes to proceed normally. The mutidrug-resistant (MDR) phenotype is also responsible for acquired resistance to taxanes. This MDR phenotype involves the amplification of P-glycoprotein membrane which functions as a drug efflux pump.

Paclitaxel was initially approved by the U.S. Food and Drug Administration (FDA) in December 1992 for use in patients with drug refractory or relapse of epithelial cancer of the ovary. In the study conducted at Johns Hopkins, 30% of 40 evaluable patients gave answers entirely major (complete and partial responses). Answer raking 1-15 months (median, 6 months). Most patients, including actors, has been widely prior chemotherapy and radiotherapy.