Multidrug resistance (MDR) is a major cause of treatment failure in acute myeloid leukemia (AML). MDR is frequently associated with energy-dependent drug efflux, and efflux may be blocked by competitive inhibition with non-cytotoxic substrates, termed MDR modulators. Pharmacological modulation of MDRis effective in laboratory models, but clinical application has been disappointing. Trials of pharmacological modulation of MDR in AML have targeted P-glycoprotein (Pgp), the best-characterized MDR-associated transport protein, but additional transport proteins, including muitidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP), are also likely to contribute to the clinical MDR phenotype. Pharmacological MDR modulation also promotes apoptosis independently of drug efflux, but this effect remains largely unexplored. The overall goal of this proposal is to develop clinical MDR modulation approaches in AML which take into account both the multiple efflux proteins expressed in AML cells and the drug efflux-independent effects of modulators. This requires determining the relevance of expression and function of MRP-1 and BCRP, in addition to Pgp, in AML and the spectrum of activity of available clinically applicable modulators. The studies will utilize the existing Cancer and Leukemia Group B (CALGB) repository of pre-treatment samples from patients > 60 years old with AML occurring de novo and following antecedent myelodysplastic syndromes, a population with a high incidence of clinical MDR, treated on a single protocol, CALGB9720.
The specific aims are: 1. To determine the incidence and clinical significance of Pgp, MRP-1 and BCRP expression and function in an AML patient population with a high incidence of clinical drug resistance; 2. To compare the effects of diverse available clinically applicable modulators, including PSC-833, cyclosporine A, Biricodar (VX-710), VX-853, the fumitremorgin C analogue KO143, and the novel taxane-derived agents IDN5109 and tRA96023, on drug retention in AML cells that have been characterized with respect to Pgp, MRP-1 and BCRP expression and function; 3. To compare the drug transport-independent effects of PSC-833, cyclosporineA, biricodar, VX-853, KO143, IDN5109 and tRA96023, onAML cell survival, measured by the apoptotic response. The study is expected to provide essential information for the design of future clinical trials of broad-spectrum MDR modulation in AML and other malignancies. ? ?
