Altered multidrug resistance phenotype caused by anthracycline analogues and cytosine arabinoside in myeloid leukemia

The expression of P-glycoprotein (Pgp) is often increased in acute myeloid leukemia (AML). However, little is known of the regulation of Pgp expressio n by cytotoxics in AML. We examined whether Pgp expression and function in leukemic blasts was altered after a short exposure to cytotoxics. Blasts we re isolated from 19 patients with AML (15 patients) or chronic myeloid leuk emia in blastic transformation (BT-CML, 4 patients). Pgp expression and fun ction were analyzed by flow cytometric analysis of MRK 16 binding and Rhoda mine 123 retention, respectively. At equitoxic concentrations, ex vivo expo sure for 16 hours to the anthracyclines epirubicin (EPI), daunomycin (DAU), idarubicin (IDA), or MX2 or the nucleoside analogue cytosine arabinoside ( AraC) differentially upregulated MDR1/Pgp expression in Pgp-negative and Pg p-positive blast cells. In Pgp-negative blasts, all four anthracyclines and AraC significantly increased Pgp expression (P = .01) and Pgp function (P = .03). In contrast, MX2, DAU, and AraC were the most potent in inducing Pg p expression and function in Pgp positive blasts (P < .05). A good correlat ion between increased Pgp expression and function was observed in Pgp-negat ive (r = .90, P = .0001) and Pgp-positive blasts (r = .77, P = .0002). This increase in Pgp expression and function was inhibited by the addition of 1 mu mol/L PSC 833 to blast cells at the time of their exposure to these cyt otoxics. In 1 patient with AML, an increase in Pgp levels was observed in v ivo at 4 and 16 hours after the administration of standard chemotherapy wit h DAU/AraC. Upregulation of Pgp expression was also demonstrated ex vivo in blasts harvested from this patient before the commencement of treatment. I n 3 other cases (1 patient with AML and 2 with BT-CML) in which blasts were Pgp negative at the time of initial clinical presentation, serial samples at 1 to 5 months after chemotherapy showed the presence of Pgp-positive bla sts. All 3 patients had refractory disease. Interestingly, in all 3 cases, upregulation of Pgp by cytotoxics was demonstrated ex vivo in blasts harves ted at the time of presentation. These data suggest that upregulation of th e MDR1 gene may represent a normal response of leukemic cells to cytotoxic stress and may contribute to clinical drug resistance. (C) 1999 by The Amer ican Society of Hematology.