Pharmacologic circumvention of multidrug resistance.
The ability of malignant cells to develop resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of clinical tumors. The phenomenon multidrug resistance (MDR) in cancer cells results in cross-resistance to a broad range of structurally diverse antineoplastic agents, due to outward efflux of cytotoxic substrates by the mdr1 gene product, P-glycoprotein (P-gp). Numerous pharmacologic agents have been identified which inhibit the efflux pump and modulate MDR. The biochemical, cellular and clinical pharmacology of agents used to circumvent MDR is analyzed in terms of their mechanism of action and potential clinical utility. MDR antagonists, termed chemosensitizers, may be grouped into several classes, and include calcium channel blockers, calmodulin antagonists, anthracycline and Vinca alkaloid analogs, cyclosporines, dipyridamole, and other hydrophobic, cationic compounds. Structural features important for chemosensitizer activity have been identified, and a model for the interaction of these drugs with P-gp is proposed. Other possible cellular targets for the reversal of MDR are also discussed, such as protein kinase C. Strategies for the clinical modulation of MDR and trials combining chemosensitizers with chemotherapeutic drugs in humans are reviewed. Several novel approaches for the modulation of MDR are examined.
Ford
J M
JM
Division of Oncology, Stanford University Medical Center, CA 94305.
Hait
W N
WN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D002147:Calmodulin; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D013256:Steroids; C009667:vindoline; D014747:Vinblastine