Multidrug resistance in cancer: role of ATP–dependent transporters

Key Points Multidrug resistance of cancer cells is a potentially surmountable obstacle to effective chemotherapy of cancer. ATP-binding cassette (ABC) transporters, including MDR1 (ABCB1), MRP1 (ABCC1) and ABCG2, can confer multidrug resistance to cancer cells in vitro . MRP2 (ABCC2), MRP3 (ABCC3), MRP4 (ABCC4), MRP5 (ABCC5), ABCA2 and BSEP (ABCB11) are capable of transporting drugs; future studies are needed to determine a role in drug resistance. ABC transporters such as MDR1 and MRP1 are expressed in many human cancers, including leukaemias and some solid tumours; in some studies, expression of these transporters has been shown to correlate with response to therapy and survival. Inhibitors of ABC transporters such as MDR1/P-glycoprotein have been tested in clinical trials with a suggestion of benefit, especially in acute myelogenous leukaemia. Interpretation of clinical trials using inhibitors of MDR1/P-glycoprotein has been confounded by their effects on the pharmacokinetics of anticancer drugs. Development of inhibitors of ABC transporters should focus on potency and specificity to minimize unexpected pharmacokinetic effects. Efficacy should be confirmed using surrogate assays. Normal tissues might be protected from toxicity by gene transfer of drug-resistance genes. Prevention of ABC transporter induction in cancer cells might help to avert drug resistance.