Anthracycline Resistance

Abstract

The major limitation of the usefulness of anthracyclines is the development of drug resistance. Most of the data related to anthracycline resistance has been obtained in experimental animal tumors or in cultured human cell lines. An important characteristic obtained in these models is the common finding of cros-resistance to a series of drugs structurally unrelated to the anthracyclines and with a mechanism of action which apparently differ from that of the anthracyclines. This phenomenon is defined as pleiotropic drug resistance or multidrug resistance (MDR). the cross-resistance demonstrated includes the vinca alkaloids. acti-nomycin D, colchicin and the epipodophyllotoxins. the best documented mechanism of resistance and mechanism of cross-resistance is decreased cellular drug accumulation. Several findings indicate that the underlying factor of the altered net uptake is an active drug extrusion in the resistant cells. Another important characteristic is the demonstration of a cell surface protein with a molecular weight of about 170000 (GP 170). Genetic and biochemical evidence indicate that the MDR phenotype in both animal and human cells result from overexpression of the MDR-I gene which encodes GP 170. Some findings suggest that GP 170 is a transport protein for cytotoxic hydrophobic drugs like the anthracyclines. Other findings suggest that this gene is also associated with intrinsic (natural) anthracycline resistance.