engleski

The relevance of multidrug resistance-associated Pgp expression and function in responses to Glivec

Background. Glivec is among the most promising and selective inhibitors of Bcr-ABL tyrosine kinase activity in chronic myeloid leukemia (CML). The mechanism of resistance to Glivec is yet unknown. Although published data on resistance to Glivec are very limited, the overexpressed P-glycoprotein (Pgp) in some resistant cells may indicate that Pgp can operate in response and be another reason for reduced sensitivity (1). The objective was to evaluate the influence of Glivec on the expression and function of Pgp and its correlation to the treatment outcome. Design and methods 14 patients aged >22 years with advanced CML /4 blast crisis (BC), 9 accelerated phase (AP) and 1 in chronic phase/ were monitored in 3 months intervals. Previous treatment included cytoreductive HU and Ara-C followed by progressive doses of IFa. Patients were eligible if they were in the chronic phase of Ph+CML and had not responded or showed intolerance to IFa therapy, or if they were in accelerated phase and blast crisis of Ph+CML. Glivec was administered as oral monotherapy: 600mg daily for BC and AP and 400 mg/day for patients in chronic phase, respectively. Due to haematologic adverse reaction in 6 patients the dose was reduced. To determine the changes in Pgp phenotype, bone marrow and peripheral blood cells were stained simultaneously with anti-HLA-DR/Pgp mAbs (Becton Dickinson) and the result was expressed as the ratio of mean fluorescences (RMF) of anti-Pgp and FL2 control. Pgp activity was assessed by comparing the uptake/efflux rates of rhodamine (Rh123) together with Pgp-reversing agent Cyclosporine A. Results Our preliminary results indicate that the changes in Pgp phenotype and function may influence the response to Glivec treatment. Although none of Pgp-inactive patients underwent clinical relapse while Pgp+ and active patients did relapse, due to short-term follow-up those differences did not reach statistical significance. Conclusion Pgp can be one of the new mechanisms of resistance to Glivec. From the prognostic point of view, functional Rh 123 screening may be helpful in determination of Glivec-resistant phenotypes. (1) Blood 2000 ; 96:1070-9

Glivec; MDR

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