Relevance of multidrug resistance proteins on the clinical efficacy of cancer therapy.

Variations in drug uptake and efflux, as well as changes in intracellular drug entrapment and distribution may represent important resistance mechanisms to cancer therapy. A variety of ATP binding cassette transporters (ABC) localised in multiple cell membranes is implied in those phenomena, representing a mechanism of protection of cells against xenobiotics. Many cancer cell lines over express some ABC transporters, especially p-glycoprotein, MRP1 and BCRP. This over expression is related to worse cancer treatment outcome and, in some cases, reduced overall survival of cancer patients. This paper reviews the location and physiological role of the three transporters mentioned and also describes the drugs that are substrates of these proteins. The usefulness of animal and cellular models to evaluate the role of these transporters on the uptake and efflux of anticancer drugs is discussed. Finally, the results of preclinical and clinical studies about the utility of some inhibitors of these pumps, as well as the implications of polymorphism of ABC transporters on the efficacy and safety of anticancer therapeutics are reported.