Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents
Open Access
- 1 July 2007
- journal article
- review article
- Published by Elsevier BV in Annals of Oncology
- Vol. 18 (suppl_5), v3-v8
- https://doi.org/10.1093/annonc/mdm172
Abstract
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.Keywords
This publication has 38 references indexed in Scilit:
- Targeting multidrug resistance in cancerNature Reviews Drug Discovery, 2006
- The Microtubule Stabilizing Agent Discodermolide is a Potent Inducer of Accelerated Cell SenescenceCell Cycle, 2005
- Molecular mechanisms of drug resistanceThe Journal of Pathology, 2005
- Microtubules as a target for anticancer drugsNature Reviews Cancer, 2004
- Microtubules become more dynamic but not shorter during preprophase band formation: A possible “search‐and‐capture” mechanism for microtubule translocationCell Motility, 2004
- Alteration of Microtubule Dynamic Instability during Preprophase Band Formation Revealed by Yellow Fluorescent Protein–CLIP170 Microtubule Plus-End Labeling[W]Plant Cell, 2003
- Molecular Dissection of the Microtubule Depolymerizing Activity of Mitotic Centromere-associated KinesinJournal of Biological Chemistry, 2001
- Differential Binding Regulation of Microtubule-associated Proteins MAP1A, MAP1B, and MAP2 by Tubulin PolyglutamylationJournal of Biological Chemistry, 2001
- Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues.Journal of Histochemistry & Cytochemistry, 1990
- Dynamic instability of microtubule growthNature, 1984