engleski

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

Gleevec is among the most promising highly selective inhibitors of fusion Bcr-Abl tyrosine kinase activity in chronic myeloid leukemia (CML) cells. A possible mechanisms of resistance to Gleevec are yet unknown. Although published data 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 the reduced sensitivity (1). Objective: To evaluate the influence of Gleevec on the expression level and function and its correlation to the treatment outcome. Design and methods: Fourteen patients aged >22 yrs 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 IFN-alpha. Patients were eligible if they were in the chronic phase of Ph+CML and had not responded or showed intolerance to IFN-alpha therapy, or if they were in accelerated phase and blast crisis of Ph+CML. Gleevec was administered as oral monotherapy: 600 mg daily for BC and AP and 400 mg/day for patients in chronic phase, respectively. Due to toxicity 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 and Pgp monoclonal antibodies (Becton Dickinson) and the results were expressed as the ratio of mean fluorescences (RMF) of specific anti-Pgp and FL2 isotype control fluorescence. Pgp activity was assessed by comparing the uptake/efflux rates of Pgp-related rhodamine dye (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 Gleevec 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: One of the new mechanisms of resistance to Gleevec therapy in CML can be Pgp-associated. From the prognostic point of view, screening of changes in Pgp phenotype and function may be helpful in determination of Gleevec-resistant phenotypes. (1) Blood 2000; 96:1070-9

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