DEVELOPMENT OF HUMAN LEUKEMIA U-937 CELL SUBLINES RESISTANT TO DOXORUBICIN - INDUCTION OF DIFFERENTIATION AND ALTERED SENSITIVITIES TO TOPOISOMERASE-DIRECTED DRUGS

Cell sublines resistant to doxorubicin (DOX) were developed from the h uman leukemia cell line, U-937/WT, exposed to stepwise DOX increases. In contrast to U-937/WT cells, the DOX-resistant U-937/RD cells have l onger doubling time; are more differentiated along the monocytic linea ge as determined by the presence of morphological features and mRNA co ding for the monocyte colony-stimulating factor-1 receptor; synthesize the apoptosis-associated Bax protein; are less sensitive to apoptosis -inducing topoisomerase II-directed drugs, apparently because of incre ase synthesis of P-glycoprotein; and are practically non-tumorigenic w hen xenografted in nude mice. However, U-937/WT and U-937/RD cells exh ibit similar sensitivity to the apoptosis-inducing drug 9-nitrocamptot hecin. These findings suggest that several mechanisms are involved in the development of DOX-resistance in U-937 cells, and further, 9-nitro camptothecin can overcome resistance to DOX. These findings may have c linical implications.