DAUNORUBICIN UPTAKE BY LEUKEMIC-CELLS - CORRELATIONS WITH TREATMENT OUTCOME AND MDR1 EXPRESSION

The in vitro daunorubicin (DNR) cell uptake was investigated by flow c ytometry in K562/DOX resistant cell line and in 42 patients with acute myeloid leukemia (AML). The proportion of cells able to take up DNR w as higher in untreated patients (50% +/- 30) than in previously treate d patients (31% +/- 31) (p = 0.04). We noted a good correlation (p < 0 .001) between the drug uptake after exposure to 0.1 muM DNR and achiev ement of complete remission. Cyclosporin A (CsA, 1 mug/ml) and verapam il (5 mug/ml), but not cefoperazone (10 mM), completely reversed (CsA) or partially reversed (verapamil) the DNR efflux from K562/DOX mdr1() cell line. CsA significantly increased (p < 0.01) the DNR uptake of fresh leukemic cells, but not consistently, with no relationship to md r1 mRNA cellular level. This absence of correlation was explained by t he fact that several patients with no mdr1 gene expression exhibited a low in vitro DNR uptake, showing that the MDR phenotype is not the on ly mechanism responsible for the alteration of DNR pharmacokinetics in AML.