engleski

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

Background. Gleevec (Imatinib mesylate) is among the most promising and selective inhibitors of Bcr-ABL tyrosine kinase activity in chronic myeloid leukemia (CML) but seemingly disappointing, like conventional cancer drugs can develop drug resistance. The mechanism of resistance to Gleevec is yet unknown. Although published data on resistance to Gleevec 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 Gleevec monotherapy on the expression and function of Pgp and its correlation to the treatment outcome. Design and methods 22 patients with advanced CML [5 blast crisis (BC), 11 accelerated phase (AP) and 6 in chronic phase (CP)] were monitored between July 2001 and November 2002 in 3 months intervals. Previous treatment included cytoreductive hydroxyurea and Cytarabine followed by progressive doses of alpha-interferon (IFalpha). Patients were eligible if they were in the CP of Ph+CML and had not responded or showed intolerance to IFalpha therapy, or if they were in AP and BC of Ph+CML. Gleevec was administered as oral monotherapy: 600mg daily for BC and AP and 400 mg/day for patients in CP, respectively. Three patients died, 4 were excluded from the therapy due to haematologic adverse reaction and 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 and the result was expressed as the ratio of mean fluorescences (RMF) of anti-Pgp and isotypic 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 Gleevec treatment. None of Pgp-inactive patients underwent clinical relapse while Pgp-positive and active patients did relapse. However, because of small number (4) of patients followed through 15 months, those differences did not reach statistical significance. Conclusion Pgp can be one of the new mechanisms of resistance to Gleevec. From the prognostic point of view, functional Rh123 screening may be helpful in determination of Gleevec-resistant phenotypes. (1) Blood 2000 ; 96:1070-9

nije evidentirano

nije evidentirano