engleski

Long-term follow-up of Pgp-related multidrug resistance in chronic myeloid leukemia patients undergoing Glivec therapy. The prognostic value of increased Pgp activity

BACKGROUND: The Bcr-Abl tyrosine kinase, the product of the chimeric gene of the Philadelphia chromosome, is the molecular abnormality that causes chronic myeloid leukemia (CML). Although Glivec (imatinib mesylate, signal transduction inhibitor STI 571 of Bcr-Abl tyrosine kinase) represents successful treatment strategy in 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 P-glycoprotein (Pgp) related multidrug resistance might influence the response to Glivec treatment. OBJECTIVE: to evaluate, in long-term follow up, Pgp expression and activity in CML patients treated with Glivec and to estimate the occurrence of MDR and its correlation to the treatment outcome. DESIGN AND 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. Glivec 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. Bone marrow (BM) and peripheral blood (PB) cells were stained simultaneously with anti HLA-DR/Pgp moAbs and the Pgp phenotype was expressed as the ratio of mean fluorescences (RMF) of specific antibodies and isotype control. Pgp activity was measured with specific Pgp-modulator Cyclosporine (CsA) by comparing uptake/efflux rates of Pgp related Rhodamine dye (Rh123) with reversing agent and the function was expressed as RMF comparing the mean (green) fluorescence of Rh123 in CsA and CsA-free sample. RESULTS: During the therapy eight patients died. In those patients the Rh123 test showed increased Pgp activity (RMF>1) in BM and PB We found lower Pgp activity in 16 responding patients, but after two year follow up study we observed a tendency to Pgp activity increase, which indicates the disease severity in those patients. CONCLUSION: Increased Pgp activity in resistant and reactivated patients is associated with chemoresistance to further therapy. Our results indicate the importance of longitudinal follow up of Pgp activity. Functional assay of Rh123 transport activity may be used as sensitive prognostic for clinical practice in the menagement of CML.

Pgp; Glivec; CML

nije evidentirano