Multidrug resistance in leukemias: the problem and some approaches to its circumvention

RESUMO

The phenomenon of multidrug resistance (MDR), representing cross-resistance among a number of unrelated chemotherapeutic drugs, is the major cause of chemotherapy failure in many tumors. It has been also detected in leukemias and in these cancers, as well as in many others, resistance can be reversed by a number of substances known as modulators or reversing agents. The capacity of identifying tumors resistant to chemotherapy could orientate the treatment employed. In leukemias, tumor cells are easily obtainable and many techniques have been used to evaluate resistance in these cells. Studying 42 leukemia patients we found a correlation of nearly 60 per cent among surface expression of P-glycoprotein, in vitro resistance reversal by cyclosporin A (CS-A) and extrusion of the rhodamine 123 dye. This latter assay has the advantage of measuring a functional aspect related to resistance (intracellular drug accumulation), being reproducible and affordable by most laboratories. The data generated by this assay were in accordance with those reported by other authors using different methods. To allow for an experimental approach in the study of MDR in leukemias, an in vitro model of a vincristine-induced erythroleukemia resistant cell line was established by us, and was shown to display MDR characteristics resistance to unrelated drugs, surface expression of P-glycoprotein, extrusion of rhodamine 123 and resistance reversal by trifluoperazine, a reversing agent. Furthermore, this vincristine-resistant line was as sensitive to cell mediated lysis by natural killer (NK) cells as the parental line. Models like this one allow for the in vitro testing of new reversing agents, and when combined to in vitro tests for NK and LAK activity, may select for substances capable of modulating resistance without affecting a potentially useful cell mediated immunotherapy.