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

Abstract

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.

Low level of DNA repair in human chromosome 1 heterochromatin

“…To achieve this goal, repair sites were selectively converted to chromosome breaks by using Ara-C, a competitive inhibitor of the DNA polymerases (Mirzayans et al, 1994). Previous studies showed that Ara-C blocks not only de novo semiconservative DNA synthesis by incorporating itself to nascent strands, but also DNA repair of lesions induced by UV light and other genotoxic agents (reviewed in Mirzayans et al, 1994).…”