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Low levels of residual disease in CML are associated with low molecular level of oncogene BCR-ABL chimeric genes and low Pgp activity

We have previously shown that the multidrug resistance (MDR) is associated with poor treatment outcome and that IM (imatinib mesylate) can induce MDR in chronic myelogenous leukemia (CML). The best known resistance mechanism is associated with activity of P-glycoprotein (Pgp) membrane transporter which decreases treatment success through amplified efflux of IM. Twenty five patients were diagnosed with chronic phase CML at Clinical Hospital Dubrava and were closely monitored over the period of six years (2004-2010). In order to elucidate the mechanism of MDR induction we evaluated the effect of IM monotherapy (400-600mg/day) by comparing the variations in the activity of Pgp pump with molecular response kinetics. Pgp activity of bone marrow and peripheral blood cells was observed by flow cytometry and the results were expressed as the ratio of minimal and real pump activity (RMF, where RMF>1 expressed elevated activity). The kinetics of molecular response was measured by qRT-PCR method and the results were divided in 4 groups: R1= complete molecular remission (PCR negative), R2= major molecular response (MMR) (<0, 1% BCR-ABL/ABL), R3= minimal molecular response (mMR) (0, 1-1% BCR-ABL/ABL) and R4= without response (>1% BCR-ABL/ABL). Nine patients were in R1 (36, 0%), 2 in R2 (8, 0%), 4 in R3 (16, 0%) while 4 patients were in group R4. Four patients died during the study (16, 0%). The results are absent for 2 patients who entered the study recently. All R1 patients had low Pgp activity whereas the greatest activity increase was observed in R4 group. During the study, 7 out of 11 patients with ratios of BCR-ABL/ABL <0, 1%, were in continuous complete molecular remission and their Pgp activity was continuously low. These results confirm the link between Pgp activity and molecular response. We conclude that rhodamine test of Pgp activity has clinical value and correlates with the BCR/ABL oncogene changes during therapy with IM indicating that elevated Pgp activity acts as unfavorable prognostic factor.

Rhodamine test; Pgp activity; BCR-ABL; CML; imatinib mesylate

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