Paclitaxel And Cancer
by Paul Kanute
Paclitaxel, a plant product from Taxus brevifolia, is a novel 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 for patients with metastatic breast cancer who failed to response to prior chemotherapy with standard agents.
Paclitaxel, the first organic compound with a taxane ring tha
t has been demonstrated to possess antineoplastic activity, was isolated in 1967 from the bark of the Western yew, Taxus brevifolia. Its mechanism of action is unique among antineoplastic agents. Paclitaxel promotes the assembly and stabilization of microtubules which are intracellular structures vital to mitosis and other critical cell functions. In contrast to other clinical useful antimicrotubules agents such as the vinca alkaloids and colchicines, which induce net disassembly by microtubules, paclitaxel shifts the equilibrium towards microtubule assembly. The binding site for paclitaxel on microtubules also appears to be distinct from other antimicrotubule agents. It binds preferentially to the beta subunit in the microtubule, rather than tubulin dimmer. Paclitaxel induces several unique morphologic effects on intracellular microtubules, including microtubules binding that occurs during all cell cycle phases and numerous abnormal mitotic asters. Two mechanisms of acquired resistance to the taxanes have been characterized. The resistance cell lines lack normal microtubules in their mitotic spindles and have inherently slow rate of microtubules assembly when grown in the absence of drug and require the continuous presence of the taxanes in order to proceed normally. The mutidrug-resistant (mdr) phenotype is also responsible for acquired resistance to taxanes. This mdr phenotype involves the amplification of membrane p-glycoprotein that functions as a drug efflux pump.
Paclitaxel was initial approved in United States by the Food and Drug Administration (US FDA) in December 1992 for use in patients with drug-refractory or recurrent epithelial ovarian cancer. In the study performed at Johns Hopkins, 30% of 40 fully evaluable patients had major responses (partial and complete responses). Response raking from 1 to 15 months (median, 6 months). Most of the patients, including responders, had received extensive prior treatments with chemotherapy and radiation.
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