Induction of sister chromatid exchanges by the thymidine analog 5-hydroxymethyl-2'-deoxyuridine

The thymidine analog, 5-hydroxymethyl-2'-deoxyuridine (hmdUrd), was tested for its ability to induce sister chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells. When tested, hmdUrd was found to be a potent inducer of SCEs in CHO cells under nontoxic conditions. Under these same conditions, hmdUrd was found to be nonmutagenic, as no increase above the background frequency of 6-thioguanine-resistant mutants was observed. The induction of SCEs by hmdUrd was suppressed by thymidine. Simultaneous exposure of the cells to low concentrations of hmdUrd and to high concentrations of the free pyrimidine 5-hydroxymethyluracil (hmUrd), which had no effect alone, had a strong synergistic effect on the induction of SCEs. Simultaneous exposure of cells to hmdUrd and to 3-aminobenzamide, a potent inhibitor of poly(ADP-ribose) polymerase, was found to increase the level of SCEs induced by the hmdUrd. These findings support the hypothesis that the formation of hmUra residues in DNA may be an important factor in the genotoxicity of radiation and oxidative damage in mammalian cells.