GROWTH-INHIBITORY PROPERTIES OF NOVEL ANTHRACYCLINES IN HUMAN LEUKEMIC-CELL LINES EXPRESSING EITHER PGP-MDR OR AT-MDR

The objective of the experiments reported in this paper was the identi fication of promising anthracycline analogs on the basis of lack of cr oss-resistance against tumor cells presenting either P-glycoprotein mu ltidrug resistance (Pgp-MDR) or the altered topoisomerase multidrug re sistant (at-MDR) phenotype. Differently modified anthracycline analogs known to be active against MDR cells were assayed in vitro against CE M human leukemic cells, and the sublines CEM/VLB(100) and CEM/VM-1 exh ibiting respectively the Pgp-MDR and the at-MDR phenotype. Two classes of molecules, in which the -NH2, group in C-3' position is substitute d with a morpholino, methoxymorpholino (morpholinyl-anthracycline), br an alkylating moiety, present equivalent efficacy in the drug-sensiti ve and the two drug-resistant sublines. These results indicate that su ch molecules may exert their cytotoxic effect through a mode of action different from that of ''classical'' anthracyclines and is not mediat ed through topoisomerase II inhibition. Both molecules represent novel concepts in the field of new anthracyclines derivatives.