The interaction between 2'-deoxycytidine (dCyd) and 1-beta-D-arabinofuranosylcytosine (
ara-C), administered at pharmacologically achievable concentrations, was examined in four continuously cultured human
leukemia cell lines, HL-60, KG-1, K-562, and CCRF-CEM. In three of the cell lines (HL-60, K-562, and CCRF-CEM), co-administration of 20 or 50 microM dCyd with 10 microM
ara-C reduced
ara-CTP formation by at least 90% and incorporation of
ara-C into
DNA by at least 80%. In contrast, KG-1 cells exhibited substantially smaller reductions in both
ara-CTP formation and incorporation of
ara-C into
DNA under identical conditions. KG-1 cells were distinguished by the highest activity of the
enzyme cytidine deaminase of the four lines assayed, and exhibited the smallest increments in the intracellular accumulation of both dCyd and
deoxycytidine triphosphate (
dCTP) in response to exogenous dCyd. Co-administration of 1 mM
tetrahydrouridine (THU) or 0.5 mM deoxy-
tetrahydrouridine (dTHU) had little effect on the ability of dCyd to antagonize
ara-C metabolism in HL-60, KG-1 and K-562 cells. In contrast, these deaminase inhibitors substantially increased the intracellular accumulation of
dCTP as well as the ability of dCyd to antagonize
ara-CTP formation and incorporation of
ara-C into
DNA in KG-1 cells. THU and dTHU also permitted dCyd to antagonize
ara-C growth inhibitory effects in KG-1 cells to the extent observed in the other leukemic cell lines. These studies suggest that the intracellular deamination of exogenous
deoxycytidine may influence the degree to which this
nucleoside antagonizes
ara-C metabolism and toxicity in some leukemic cells. They also raise the possibility that deaminase inhibitors may be employed to modulate, and perhaps to improve, the therapeutic selectivity of pharmacologically relevant concentrations of
ara-C and dCyd in the treatment of acute
leukemia in man.