Multidrug resistance

Stepwise selection of an amplified gene that codes for a transmembrane protein (P-glycoprotein for “permeability” glycoprotein is responsible for multidrug resistance. This resistance is due to adenosine triphosphate–dependent pumping of drugs out of the cell in the presence of P-glycoprotein. Crossresistance following the use of structurally unrelated agents also occurs. For example, cells that are resistant to the cytotoxic effects of the vinca alkaloids are also resistant to dactinomycin and to the anthracycline antibiotics as well as to colchicine, and vice versa. These drugs are all naturally occurring substances, each of which has a hydrophobic aromatic ring and a positive charge at neutral pH. [Note: P-glycoprotein is normally expressed at low levels in most cell types, but higher levels are found in the kidney, liver, pancreas, small intestine, colon, and adrenal gland. It has been suggested that the presence of P-glycoprotein may account for the intrinsic resistance to chemotherapy observed with adenocarcinomas.] Certain drugs at high concentrations (for example, verapamil) can inhibit the pump and, thus, interfere with the efflux of the anticancer agent. However, these drugs are undesirable because of adverse pharmacologic actions of their own. Pharmacologically inert pump blockers are being sought.