ABC transporters and inhibitors: new targets, new agents.
P-glycoprotein (P-gp), a plasma membrane pump associated with multidrug resistance (MDR), is a member of the superfamily of ATP-binding cassette (ABC) transporters. The discovery that inhibitors of drug efflux can increase drug accumulation and reverse drug resistance in the laboratory has led to the clinical development of a number of P-gp inhibitors. Initial studies were performed with agents already in use in the clinic for other indications, the 'first generation' studies. Second generation inhibitors were taken into clinical trials in leukemia, breast cancer, ovarian cancer and sarcoma, malignancies for which there is evidence that P-gp is expressed, and in some cases, associated with a poorer therapeutic outcome. One major limitation of these trials, however, was the reduction in anticancer drug doses that was required with concurrent administration of inhibitor. The reduction in drug dose needed in these combination studies, may have confounded the results and contributed to disappointing outcomes. Functional assays to verify the role of P-gp inhibition in MDR, such as sestamibi imaging are proving helpful in assessing the development of improved inhibitors that are providing hope for the future. This review focuses on attempts aimed at overcoming resistancemediated by ABC transporters and evaluates the prospects for addition of new inhibitors to the anticancer armamentarium.
Leonard
Gregory D
GD
Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, Bldg 10 Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20814, USA.
Polgar
Orsolya
O
Bates
Susan E
SE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D016503:Drug Delivery Systems / Q000379:methods*; D018432:Drug Resistance, Multiple / Q000502:physiology; D006801:Humans
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents