Pharmacologic approaches to reversing multidrug resistance.

The rationale for modulation of multidrug resistance (MDR) by inhibitors of the multidrug transporter, P-glycoprotein (P-gp) includes the following: (1) P-gp is expressed by human cancers, either at diagnosis or after failure of chemotherapy; (2) P-gp expression at diagnosis has been associated with a poor prognosis in some types of cancer; (3) MDR related to P-gp expression can be reversed by modulators, resulting in enhanced therapeutic efficacy in cellular and animal models of drug resistance; and (4) the emergence of MDR related to P-gp expression can be prevented in cellular models by co-administration of MDR-related cytotoxins and modulators. Clinical trials of modulation of MDR have been limited by two major factors: inability to achieve adequate levels of the modulators to reverse drug resistance in patients and the presence of other mechanisms of resistance in tumor cells in addition to P-gp. The former limitation will hopefully be overcome by new, more potent and specific inhibitors of P-gp such as PSC 833. The latter will require further understanding of various alternative cellular mechanisms of resistance and the development of approaches to overcome or circumvent these mechanisms. PSC 833 is associated with significant drug interactions with MDR-related cytotoxic agents, which require dose reduction of the cytotoxins to achieve a dose exposure and toxicity similar to the chemotherapy agents without a modulator. These drug interactions are predictable and are at least in part due to inhibition of P-gp in normal tissues such as the liver and kidneys, where P-gp is known to play a role in drug excretion. Data from knockout mice, which lack P-gp expression, support the concept that P-gp is an important factor in MDR-related drug disposition. Early data from phase I and II trials with PSC 833 indicate that substantial inhibition of P-gp can be achieved in patients at clinically tolerable doses of both modulator and cytotoxins. The ultimate therapeutic benefit of MDR modulation with PSC 833 is currently being tested in phase III clinical trials in acute myeloid leukemias (AMLs) and multiple myeloma.