New and Revised Concepts in Multidrug Resistance

Abstract

Drug resistance resulting from the outward efflux of anticancer agents by ATP binding cassette (ABC) transporters such as P-glycoprotein (P-gp) has been well described in vitro in laboratory models. The extent to which multidrug transporters are responsible for clinical drug resistance has been more difficult to determine. In one sense, P-gp can be viewed as a molecular target that was tested in the clinic before there was an adequate understanding of the diseases that were best to study, and before the best inhibitors had been identified. We now recognize that several factors may have impeded the results of clinical trials testing P-gp modulators. First, inhibitors either were not sufficiently potent or required areduction in anticancer drug dose. Alternatively, the presence of other ABC transporters, such as the multidrug resistance-associated protein (MRP1) and the ABC half-transporter ABCG2, may have confounded the results. A single-nucleotide polymorphism (SNP) that limits the expression of P-gp could prevent inhibitor therapy from benefiting patients, and increase toxicity as well. The goal of this chapter is to evaluate new directions in the study of ABC transporters in multidrug resistance, offering fresh approaches to the fundamental question that asks whether ABC transporters are important molecular targets for anticancer drug development.