Doxorubicin and multidrug resistance.

The circumvention of P-glycoprotein function by pharmacologic agents is a major focus of clinical trials aimed at increasing the cytotoxicity of multidrug resistance-associated drugs, including doxorubicin. The success of this approach will likely depend on the clinical significance of P-glycoprotein expression, which has not yet been elucidated for the common solid tumors, and the ability to achieve effective levels of circumventing agents without dose-limiting toxicities. Initial clinical studies suggested that biologically relevant concentrations of multidrug resistance modulators, eg, cyclosporine, can be achieved. Because pharmacologic agents that inhibit drug efflux by P-glycoprotein are themselves pumped out of cells by the transporter, this approach may have an inherent barrier to success. Laboratory studies have suggested alternative strategies for circumventing P-glycoprotein action, eg, the use of monoclonal antibodies directed against P-glycoprotein and liposome-encapsulated drugs.