engleski

Evaluation of chemoresistance by flow cytometric measurements of Pgp function in patients undergoing Gleevec therapy

Background: Multidrug resistance (MDR) of haematologocal malignancies is major obstacle to chemotherapy cuccess. The MDR1 gene product, P-glycoprotein (Pgp) reduces cellular accumulation of different drugs. Although Gleevec (imatinib mesylate) represents successful treatment strategy in chronic myeloid leukemia (CML), some patients are inherently resistant or become resistant during the treatment. In a previous pilot study we monitored CML patients and observed that the changes in Pgp phenotype and function might influence the response to Gleevec treatment. Aim: to evaluate, in long-term follow up, Pgp function in CML patients treated with Gleevec and to estimate the occurrence of multidrug resistance and its correlation to the treatment outcome. Methods: Twenty-four patients aged  22 yrs with advanced CML [4 in blast crisis (BC), 12 in accelerated phase (AP) and 8 in chronic phase (CP)] were monitored in 3 months intervals starting with July 2001. Previous treatment included HU and IFN alpha ; only 2 patients received MDR-related Ara-C therapy. Gleevec was administered as oral monotherapy: 600 mg daily for BC and AP and 400 mg/day for patients in CP, respectively. The dose was reduced in 11 patients due to toxicity reaction. Methods: bone marrow (BM) and peripheral blood (PB) cells were stained simultaneously with Pgp-related Rhodamine dye (RH123) and Pgp reversing agent Cyclosporine (CyA) and the Pgp function was expressed as the ratio of mean fluorescences (RMF) of CyA+Rh123 and Rh123-stained samples. Results: During the therapy eight patients died. In those patients the Rh123 test showed increased activity of Pgp pump in BM and PB. We found lower Pgp activity in 16 responding patients, but after one year follow up study we observed a tendency to Pgp activity increase, which indicates appearance of chemoresistance to further therapy in those patients. Conclusion: Our results indicate the importance of longitudinal follow up of MDR status.

rezistencija na lijekove; Glivec; kronična mijeloidna leukemija

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