Molecular mechanisms of resistance to taxanes and therapeutic implications

The mechanism of resistance to taxanes has not been fully elucidated. Since Taxol is a substrate for P-glycoprotein, overexpression of this transport system is recognized as a relevant mechanism of resistance. Additional mech anisms include changes of microtubule structure and/or composition resultin g in reduced drug binding to the target. Current efforts are directed at cl arifying the role of cellular response to drug-induced damage to cytoskelet on and mitotic spindle. Downstream events, such as control of cell cycle pr ogression and regulation of cell death pathways, are likely to play a relev ant role in cellular sensitivity to antimicrotubule agents. The identificat ion of resistance factors and critical determinants of antitumor efficacy o f microtubule-stabilizing agents is essential to (i) improve their therapeu tic efficacy; and (ii) to design non-cross-resistant compounds. The present review discusses the possible therapeutic implications of the recent progr ess in the field of resistance to taxanes. (C) 1999 Harcourt Publishers Ltd .