ATP-binding cassette (ABC) proteins in untreated acute myeloid leukemia (AML) in patients 60 years and older (CALGB 9760)

Abstract

6551 Background: Drug efflux mediated by the ABC protein P-glycoprotein (Pgp) is an adverse prognostic factor and a presumed mechanism of treatment failure in older AML patients, but little is known about the other multidrug resistance (MDR)-associated ABC protein drug efflux pumps multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP). We studied these additional drug efflux mechanisms and the effects of diverse MDR modulators. Methods: Pre-treatment samples from 106 untreated AML patients 60 years and older [ages, 67 to 84 (median, 71) years; 82 (77%) de novo AML, 24 (23%) following myelodysplastic syndromes, and 4 (4%) therapy-related] were studied for expression of Pgp, MRP-1 and BCRP, for drug efflux and for modulation of drug efflux by the Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C (FTC) and by cyclosporine A (CsA) which has activity against all three proteins, by flow cytometry. Pgp, MRP-1 and BCRP expression was studied with the MRK-16, MRPm6 and BXP-21 antibodies. Flow cytometry data were analyzed by the Kolmogorov-Smirnov statistic, expressed as a D-value, with cutoffs defining expression, efflux and modulation established in cell lines. Results: Pgp, MRP-1 and BCRP were expressed in 43%, 30% and 52% of samples, and at least one protein in 86%. Pgp and BCRP, Pgp and MRP-1, and MRP-1 and BCRP were coexpressed in 38%, 16% and 31%, and all three proteins in 13% of samples. Efflux of mitoxantrone, a substrate for Pgp, MRP-1 and BCRP, was seen in 77% of samples, and was reduced by PSC-833, probenecid and FTC in 30%, 8% and 15%,and by CsA in 34%. Effects of MDR protein-specific modulators correlated poorly with MDR protein expression. Conclusions: AML cells in older patients frequently express diverse ABC proteins and frequently exhibit drug efflux, but effects of specific modulators on efflux in vitro correlate poorly with expression of specific proteins, and the modulators studied were effective in no more than half of cases in which efflux was seen. These data support ongoing efforts to develop and test broad-spectrum ABC protein modulators with efficacy in modulating all of the ABC proteins expressed in AML cells. No significant financial relationships to disclose.