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P-glycoprotein and Multidrug Resistance Protein Activities in Relation to Treatment Outcome in Acute Myeloid Leukemia

Departments of Hematology [D. M. v. d. K., E. V.] and Medical Oncology [D. M. v. d. K., E. G. E. d. V.] and Dutch-Belgian Hemato-Oncology Cooperative Group (Hovon) [E. V.], University Hospital Groningen, Groningen, the Netherlands; Department of Biostatistics, Daniel den Hoed Cancer Center, University Hospital Rotterdam, Rotterdam, the Netherlands [W. L. J. v. P.]; Department of Hematology, University Hospital Utrecht, Utrecht, the Netherlands [L. F. V.]; Free University Hospital Amsterdam, Amsterdam, the Netherlands [G. J. O.]; and Department of Hematology, University Hospital Leuven, Leuven, Belgium [G. E. G. V.]

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 flow cytometric assay using rhodamine 123 (Rh123) in combination with PSC833 and carboxyfluorescein (CF) 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 CF 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 CF 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).

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