Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents.
Antimitotic agents that target the dynamic equilibrium between the microtubule polymer and tubulin heterodimers are key components of chemotherapeutic regimens for various solid tumors. These agents can be divided into two major classes based on their effect on microtubule polymerization and the mass of microtubule polymers: those that inhibit polymerization, such as the vinca alkaloids and those that stabilize microtubules, such as the taxanes and epothilones. The taxanes paclitaxel (Taxol) and docetaxel (Taxotere) were the first antimicrotubule agents approved for use in solid tumors, but their usefulness is often limited by development of drug resistance. The epothilones are distinguished from the taxanes structurally and functionally and have been shown in vitro and in preclinical models to have superior potency to the taxanes. The epothilones are not susceptible to P-glycoprotein-mediated efflux and have shown activity against taxane-resistant tumors. Other natural-product microtubule-stabilizing agents also have promising pharmacologic profiles. This article discusses mechanisms of drug resistance and summarizes scientific and clinical data supporting the potential of novel microtubule-stabilizing agents for achieving broad antitumor efficacy without the emergence of drug resistance. The ability to reduce the development of resistance with the epothilones and other microtubule-stabilizing agents may provide additional treatment options at the time of presentation and in the setting of taxane resistance.
Fojo
T
T
National Cancer Institute, Bethesda, MD 20892, USA. tfojo@helix.nih.gov
Menefee
M
M
D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D034261:Epothilones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
D034261:Epothilones; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel; D017239:Paclitaxel