P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia

Abstract

Despite treatment with intensive chemotherapy, a considerable number of patients with acute myeloid leukemia (AML) die from their disease due to the occurrence of resistance. Overexpression of the transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP) 1 has been identified as a major cause of cross-resistance to functionally and structurally unrelated drugs, In the present study, the functional activity of P-gp and MRP was determined in 104 de novo AML patients with a pow cytometric assay using rhodamine 123 (Rh123) in combination with PSC833 and carboxyfluorescein (CP) in combination with MK-571, The results were compared with clinical outcome and with known prognostic factors. The functional activity of P-gp and MRP, expressed as Rh123 efflux blocking by PSC833 and CF efflux blocking by MK-571, demonstrated a great variability in the AML patients. A strong negative correlation was observed between Rh123 efflux blocking by PSC833 and Rh123 accumulation (r(s) = -0.69, P <0.001) and between CP efflux blocking by MK-571 and CF accumulation (r(s) = -0.59, P <0.001), A low Rh123 accumulation and a high Rh123 efflux blocking by PSC833 were associated with a low complete remission (CR) rate after the first cycle of chemotherapy (P = 0.008 and P = 0.01, respectively). Patients with both low Rh123 and CF accumulation (n = 16) had the lowest CR rate (6%), whereas patients with both high Rh123 and CP accumulation (n = 11) had a CR rate of 73%, AML patients with French-American-British classification M1 or M2 showed a lower Rh123 accumulation than patients with French-American-British classification M4 or M5 (P = 0.02), No association was observed between the multidrug resistance parameters and overall survival of the AML patients. Risk group was the only predictive parameter for overall survival (P = 0.003)