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Multidrug resistance in multiple myeloma: Correlation of Pgp fluorescence intensity and rhodamine efflux with clinical characteristics

Background: Multidrug resistance (MDR) of haematological malignancies is a major obstacle to chemotherapy success. The MDR1 gene product, P-glycoprotein (Pgp) reduces cellular accumulation of different drugs such as vinca alkaloids and antracyclines in leukaemia, whereas less contribution to resistance in multiple myeloma (MM) has been demonstrated. Aim: Since Pgp-dependent drugs Vincristine (V) and Adriamycine (A) are administred in MM treatment, the aim of this study was to compare Pgp phenotype and drug transport activity with clinical data and therapy outcome. Design and methods: In the present study we have analysed a group of 55 consecutive MM specimens of both sexes, aged 35-80 years differing in stage and duration of the disease, as well as in the protocols and number of therapy cycles applied. Bone marrow cells were stained with mAb MRK-16 that recognises extracellular Pgp epitope and the result was expressed as the ratio of mean fluorescences (RMF) of MRK-16 mAb and FL1 control isotype. Results: In more than half of the treated patients MDR phenotype is associated with increased Pgp expression (RMF values >1.5). Moreover after therapy with two Pgp-dependent drugs (VAD and M2) RMF were higher than after treatment with one (VMCP) or no Pgp-dependent drug and (MP), but due to large range in Pgp expression in nontreated patients (RMF from 0.6 to 2.2) those differences did not reach statistical significance. In addition, Pgp expression was associated with incidence of Bence Jones proteins (p<0.05) and especially increased in advanced clinical stages for 12 patients treated with VAD or M2 (p<0.01). Furthermore, Pgp activity was assessed by comparing the uptake/efflux rates of the cationic dye rhodamine (Rh123) together with MDR reversing agent Cyclosporine A. Most importantly, concerning the functional ability of MM cells to eliminate Rh123 we report an age-dependent efflux decrease (R=­0.404, p<0.05) and increased (p<0.05) ability of MM cells to eliminate Rh123 in advanced clinical stages but the emerged MDR was not in correlation with chemotherapeutic agents exposure or therapy outcome. Conclusions: Our preliminary results indicate that MDR in MM is associated with increased Pgp expression. From the prognostic point of view, as functional Rh123 screening may not be conclusive for determination of drug resistant phenotypes, for relevant MDR factor in MM we suggest Pgp phenotype accompanied with clinical characteristics (expression at onset of disease and after Pgp-dependent drug treatment).

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