We have investigated the genotoxicity of two 3'-derivatives of
cytidine, 2,3'-O-cyclocytidine (3'-cycloC) and
beta-xylocytidine (
xyloC), in human
leukemia and solid tumor cell lines. Both derivatives were found to be cytotoxic at micromolar concentrations. For example, in the alveolar tumor cell line A549 which was included in all experiments as a reference,
drug concentrations required to induce 50% inhibition of cell growth (D50 values) equalled 55 microM for 3'-cycloC and 80 microM for
xyloC. Compared with the response of this reference cell line, none of the solid tumor cell lines tested--representing five different
malignancies--displayed significant
hypersensitivity to these drugs, while the
acute lymphoblastic leukemia cell lines proved to be hypersensitive (range of D50 values, 5-13 microM). To gain insight into the modes of cytotoxic action of
xyloC and 3'-cycloC, we compared the effect on
DNA metabolism of these compounds with that of 1-beta-D-arabinofuranosylcytosine (araC), a potent inhibitor of semi-conservative DNA replication and long-patch excision repair. As seen with araC, the xylo compound strongly inhibited both
DNA replicative synthesis and the repair of DNA damage induced by UV light and 60Co gamma-radiation. In gamma-irradiated A549 cells, the extent of repair inhibition by 1 mM
xyloC was approximately 40% of that inhibited by araC, and concomitant exposure of the irradiated cultures to
xyloC plus araC gave rise to a synergistic response. Since araC was employed at a concentration (0.1 mM) which produced a maximal effect on DNA repair when applied alone, the observed synergistic response implies that the mode of action of
xyloC on DNA repair is different from that of araC. In contrast to that observed with
xyloC, 3'-cycloC proved to be a very weak inhibitor of DNA replication and repair, strongly suggesting that the genotoxic action of the latter analog may be through a mechanism other than inhibition of
DNA synthesis.