Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein.
BACKGROUND
Multidrug resistance (MDR) is a significant obstacle to providing effective chemotherapy to many patients. Multifactorial in etiology, classic MDR is associated with the overexpression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing.


METHODS
The development of P-gp inhibitors is reviewed, including a discussion of early agents that are no longer being developed and third-generation agents that are currently in clinical trials.


RESULTS
First-generation agents (eg, cyclosporin, verapamil) were limited by unacceptable toxicity, whereas second-generation agents (eg, valspodar, biricodar) had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors (tariquidar XR9576, zosuquidar LY335979, laniquidar R101933, and ONT-093) have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on cytochrome P450 3A4 drug metabolism and no clinically significant drug interactions with common chemotherapy agents.


CONCLUSIONS
Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.
Thomas
Hilary
H
University of Surrey, Guildford, United Kingdom.
Coley
Helen M
HM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents