The role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia

Despite more effective treatment for younger patients with acute myeloid leukemia (AML), resistance to conventional antineoplastics has limited such advances in the elderly. Overexpression of the multidrug transporter, P-glycoprotein (Pgp), appears to contribute to treatment failure in de novo AML and has been detected in up to 70 percent of elderly patients. Data also indicate linkage between Pgp and many adverse prognostic features, including cytogenetic pattern, surface phenotype, and evolution from an antecedent hematologic disorder. Pharmacologic inhibitors of Pgp function have been targeted for investigation in elderly AML patients. Non-Pgp mechanisms responsible for multidrug resistance (MDR) phenotypes that are only weakly sensitive to classic Pgp modulators, however, may limit the success of such strategies. Overexpression of the lung-resistance protein (LRP) in AML has also been linked to advanced age, secondary leukemia, and Pgp overexpression. In a study of 66 patients at the Arizona Cancer Center, LRP overexpression was a more important predictor of response to induction therapy for AML than was Pgp. Recent investigations indicate that overexpression of the gene encoding the MDR-related protein (MRP), though rare in de novo AML, may be common in high-risk groups such as relapsed patients and secondary AML. Use of monoclonal antibodies specific for the MRP gene product may further define its prognostic relevance in AML.