Absence of correlation between cytotoxicity and drug transport by P‐glycoprotein in clinical leukemic cells

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Abstract
Development of resistance to cytotoxic agents is a common problem in the treatment of acute leukemia. In cell lines having multidrug resistance (MDR) phenotype, a decrease in the intracellular accumulation of drugs has been closely related to the overexpression of P-glycoprotein/mdr1 genes. We analyzed the relationship between the cytotoxicity of adriamycin (ADR) in vitro, intracellular accumulation of ADR, and the expression of P-glycoprotein on fresh leukemic cells from 19 patients at their initial presentation and from 9 relapsed patients. Pretreatment patients showed significantly higher ratio of complete remission than relapsed patients, and mean value of IC50 for adriamycin in initial presentation was higher than at relapse. But we found no significant relationship between in vitro cytotoxicity and drug transport. In addition, only 2 of the 5 relapsed patients examined by monoclonal antibody C219 expressed the P-glycoprotein. These results suggest that the acquisition of clinical drug resistance may involve various mechanisms other than the reduction of drug accumulation with P-glycoprotein expression.