Interaction of deoxycytidine and deoxycytidine analogs in normal and leukemic human myeloid progenitor cells

The inhibitory effects of three deoxycytidine analogs, 1-B-D-arabinofuranosylcytosine (Ara-C), 5-aza-2′-deoxycytidine, (DAZ) and Ara-5-azacytosine (AAC) were compared with respect to the clonogenic behavior of human promyelocytic leukemic cells (HL-60), a deoxycytidine kinase deficient subvariant (HL-60/Ara-C), and normal human myeloid progenitor cells (CFU-GM). When cells were continuously exposed to each agent for 7 days, Ara-C was the most inhibitory, DAZ slightly less effective and AAC the least inhibitory on a molar basis. HL-60/Ara-C were also highly cross-resistant to both DAZ and AAC. In the absence of deoxycytidine, all three agents were either equally inhibitory or slightly more inhibitory to the growth of CFU-GM than to HL-60, whereas administration of deoxycytidine in ten to one-hundred fold excess protected CFU-GM to a greater extent than HL-60. In contrast, administration of high concentrations of drugs, e.g. 10^-5-10^-4 M, in conjunction with excess deoxycytidine exhibited greater toxicity toward CFU-GM than toward HL-60/Ara-C. Coadministration of deoxycytidine in ten-fold excess reduced the total intracellular accumulation and DNA incorporation of each analog in HL-60 cells by approx. 50%, whereas a hundred fold excess was associated with greater than a 90% reduction in these values. These studies demonstrate that deoxycytidine may antagonize the effects of Ara-C, DAZ and AAC in both normal and leukemic human myeloid cells, and that at low drug concentrations the degree of protection may be greater for normal elements. However, regimens employing high drug concentrations in conjunction with deoxycytidine do not appear to exert a selective inhibitory effect toward a highly resistant leukemic subvariant. These data suggest that alternative deoxycytidine/deoxycytidine analog dose relationships and schedules must be sought which are capable of selectively eradicating resistant cells.