Unilateral chromatid damage: a new basis for 6-thioguanine cytotoxicity

Using the technique of premature chromosome condensation, which permits the visual inspection of interphase chromatin, we have shown previously that 28 hr after exposure to 6-thioguanine (TG) specific and drastic morphological changes in the chromosomes of Chinese hamster ovary fibroblasts in the G2 phase of the cell cycle become evident. In this paper, we demonstrate that this damage is a dose-related effect, appearing as sharp curling or "kinking" at lower TG concentrations and as unilateral chromatid damage and gross chromosome disruption at higher TG concentrations. With the use of a scoring system for quantitating the severity of this specific damage, the threshold concentrations for the appearance of unilateral chromatid damage and for loss of colony-forming ability were shown to be identical. Since the appearance of unilateral chromatid damage paralleled the appearance of TG-induced cytotoxicity in terms of time and dose, and since the severe disruption of G2 prematurely condensed chromosomes is consistent with TG-induced G2 arrest seen in this and other systems, we conclude that unilateral chromatid damage is centrally involved in the delayed cytotoxicity of TG in Chinese hamster ovary cells.