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      Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein.

      Cancer control : journal of the Moffitt Cancer Center

      Antineoplastic Agents, therapeutic use, Drug Resistance, Multiple, physiology, Drug Resistance, Neoplasm, Humans, Neoplasms, drug therapy, metabolism, physiopathology, P-Glycoprotein, antagonists & inhibitors, biosynthesis, drug effects

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          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. 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. 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. 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.

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