Comparative genotoxicity of 2,3'-O-cyclocytidine, {beta}-xylocytidine and 1-{beta}-D-arabinofuranosylcytosine in human tumor cell lines

We have Investigated the genotoxicity of two 3'-derivativesof cytidine, 2,3'-O-cyclocytidine (3'-cycloC) and ß-xylocytidine(xyloC), in human leukemia and solid tumor cell lines. Bothderivatives were found to be cytotoxic at micromolar concentrations.For example, in the alveolar tumor cell line A549 which wasincluded in all experiments as a reference, drug concentrationsrequired to induce 50% inhibition of cell growth (DM values)equalled 55 (iMfor 3'-cycloC and 80 µM for xyloC. Comparedwith the response of this reference cell line, none of the solidtumor cell lines tested—representing five different malignancies—displayedsignificant hypersensitivity to these drugs, while the acutelymphoblastic leukemia cell lines proved to be hypersensitive(range of D₅₀ values, 5–13 (µM). To gain insightinto the modes of cytotoxic action of xyloC and 3'-cycloC, wecompared the effect on DNA metabolism of these compounds withthat of 1-p-D-arabinofuranosylcytosine (araC), a potent inhibitorof semi-conservative DNA replication and long-patch excisionrepair. As seen with araC, the xylo compound strongly inhibitedboth DNA replicative synthesis and the repair of DNA damageinduced by UV light and ⁶⁰Co -radiation. In -irradiated A549cells, the extent of repair inhibition by 1 mM xyloC was 40%of that inhibited by araC, and concomitant exposure of the irradiatedcultures to xyloC plus araC gave rise to a synergistic response.Since araC was employed at a concentration (0.1 mM) which produceda maximal effect on DNA repair when applied alone, the observedsynergistic response implies that the mode of action of xyloCon DNA repair is different from that of araC. In contrast tothat observed with xyloC, 3'-cycloC proved to be a very weakinhibitor of DNA replication and repair, strongly suggestingthat the genotoxic action of the latter analog may be througha mechanism other than inhibition of DNA synthesis.