engleski

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

Pgp is multidrug resistance (MDR) glycoprotein that reduces cellular accumulation of different drugs such as vinca alkaloids and antracyclines. In multiple myeloma (MM) poor response to chemotherapy is relatively common, although it is not clear whether the Pgp expression and activity are intrinsic or chemotherapy induced. Since, in majority of MM treatments, Pgp-dependent drugs Vincristine (V) and Adriamycine (A) are administred, the aim of this study was to compare Pgp phenotype and drug transport activity with the clinical data and therapy outcome. We have analysed bone marrow (BM) specimens from a group of 55 consecutive MM patients 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. BM cells were stained with monoclonal antibody (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. 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 MDR-dependent drugs RMF were higher than after treatment with one or no MDR-dependent drug, 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 was especially increased in advanced clinical stages for 12 patients treated with two MDR-dependent therapies (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. However, the emerged MDR was not correlated to chemotherapeutic agents exposure or the therapy outcome. In conclusion, our preliminary results indicate that MDR in MM is associated with primarily 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 to consider the Pgp phenotype expression along with the time (the onset of disease and after MDR-dependent drug treatment).

nije evidentirano

nije evidentirano