Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia

In adult acute myeloid leukemia (AML), the weight of the contribution of th e combined activity of Pgp and MRP1 to drug resistance is not known. To add ress this question, we compared the activity of these proteins to the in vi tro resistance to daunorubicin (DNR), etoposide, and cytosine arabinoside ( Ara-C), using the calcein-AM uptake and the 3-[4, 5-di-methyl-thiazol-2,5-d iphenyl] tetrazolium bromide (MTT) assay in 80 adult AML patients. We found no correlation or only a weak correlation between the in vitro drug resist ance to DNR and etoposide and MRP1 or Pgp expression or function when teste d separately. However, a strong correlation was observed between the simult aneous activity of MRP1 and Pgp (quantified as the modulation of calcein-AM uptake by cyclosporin A and probenecid) and the LC50 of DNR (r=.77, P <.00 01). This emphasized the role of these two proteins, not separately, but to gether in the resistance to DNR. In contrast, Mvp/LRP expression did not co rrelate with the LC50 of DNR. A high level of simultaneous activity of Pgp and MRP1 was predictive of a poor treatment outcome (for achievement of CR [P =.008], duration of relapse-free survival [RFS; P =.01], and duration of overall survival [OS; P =.02]), In addition, high LC50 of DNR and high LC5 0 of etoposide together were also predictive of a poor treatment outcome (f or duration of RFS [P =.02] and duration of OS [P =.021). The unfavorable c ytogenetic category was more closely associated with the combined activity of both MRP1 and Pgp (P =.002) than with the activity of Pgp or MRP1 separa tely. This could explain the poor prognosis and the in vitro resistance to daunorubicin in this group of patients. These data suggest that treatment o utcome may be improved when cellular DNR and etoposide resistance can be ci rcumvented or modulated. Modulation of not only Pgp but also MRP1 could be essential to attain this aim in adult AML. (C) 1999 by The American Society of Hematology.