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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

Imatinib mesylate (IM) therapy in chronic myelogenous leukemia (CML) patients can induce multidrug resistance (MDR) which is associated with poor treatment outcome. The best known resistance mechanism is associated with activity of P-glycoprotein (Pgp) membrane transporter. Twenty five patients were diagnosed with chronic phase CML at Clinical Hospital Dubrava and were monitored over the period of six years. In order to elucidate the mechanism of MDR induction we evaluated the effect of IM monotherapy by comparing the variations in the activity of Pgp pump with molecular response kinetics. Pgp activity of bone marrow and peripheral blood cells was assessed by flow cytometry and the results were expressed as the ratio of minimal and real pump activity . The kinetics of molecular response was measured by qRT-PCR method and the results were divided in 4 groups: R1= complete molecular remission, R2= major molecular response (MMR), R3= minimal molecular response (mMR) and R4= without response. Nine patients were in R1 (36, 0%), 2 in R2 (8, 0%), 4 in R3 (16, 0%) while 4 patients were in group R4. Two patients entered the study recently and are not evaluable . All R1 patients had low Pgp activity whereas the greatest activity increase was observed in R4 group. 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 adds as unfavorable prognostic factor.

Multidrug resistance; Pgp; CML

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