ALTERED SENSITIVITIES TO ANTICANCER AND DIFFERENTIATION AGENTS IN ETOPOSIDE-RESISTANT HUMAN MYELOID-LEUKEMIA U-937 CELLS

We previously have exposed U-937 human leukemia cells to stepwise incr eased concentrations of the anticancer drug etoposide, and this treatm ent has resulted in stable sublines (termed U-937/RE) exhibiting vario us extents of resistance to the drug and constitutively expressing c-f ms mRNA, a specific marker of monocytic differentiation. In this repor t, we pursued studies to show that the P-glycoprotein blocker, verapam il, partially restores sensitivity to etoposide in U-937/RE cells, Fur ther, the U-937/RE cells exhibit differential sensitivities to compoun ds that induce maturation of U-937 cells, as judged by the ability to reduce nitroblue tetrazolium and by morphologic changes, and increased sensitivities to apoptosis induction by the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) and the anticancer drugs 9-nitrocamp tothecin and doxorubicin. In addition, the U-937/RE cells, xenografted in immunodeficient mice, demonstrate decreased or no ability to induc e tumors. Taken together, these findings indicate that U-937/RE cells differ from the parental U-937 cells in several functional properties and can serve as models to develop protocols for treatment of human le ukemia.