Microtubule targeting agents: Basic mechanisms of multidrug resistance (MDR)

Multidrug resistance (MDR) results in the loss of activity of anticancer agents against cells possessing the MDR phenotype. In some cases, tumor cells are intrinsically resistant to chemotherapeutic drugs (intrinsic resistance), while in other instances cells become resistant after exposure to cytotoxic agents (acquired resistance). MDR has a significant impact on the management of patients with solid tumors, including those with breast cancer, where it has been previously correlated with a decreased response to treatment and a poor prognosis. Taxanes are among the most important components of chemotherapy regimens to treat recurrent breast cancer. In taxane-refractory cells, the two mechanisms most commonly associated with the development of MDR are the overexpression of members of the ATP-binding cassette family of transporters, of which P-glycoprotein is the best known, and alterations of tubulin, which is the cellular target of the taxanes. In vitro and in vivo models have been developed to study the development of MDR and to assess the potential clinical application of MDR modulators. However, despite promising advances using MDR modulators in preclinical models, clinical applications have met with limited success. Novel strategies are needed to circumvent the development of drug resistance. New cytotoxic agents capable of evading MDR offer hope for patients with breast cancer. © 2005 Elsevier Inc. All rights reserved.