Cytotoxicity of 5-aza-2'-deoxycytidine in a mammalian cell system.

After the addition of 5-aza-2'-deoxycytidine, a potent inhibitor of DNA methylation and S-phase-specific cytotoxic agent, metaphase chromosomes of Chinese hamster ovary (CHO) cells exhibited a highly decondensed and extended morphology (numerous "fragile sites") at the first mitotic division. However, when a lethal dose of this drug was added in early G1 phase to cells synchronised by mitotic selection, the majority subsequently divided at the same time as an untreated control cell population with few division abnormalities and with few of the more usual types of chromosome aberrations such as gaps, breaks and exchanges. The drug-treated cells also entered and completed the second S-phase without significant delay and it was only at the second mitosis after addition of 5-azadeoxycytidine that cells showed delays in entering mitosis and significant increases in abnormal divisions concomitant with a modest increase in chromosome aberrations. If cells in a tumour behave similarly, the tumour mass would be expected to double before any reduction in tumour burden could be expected to occur.