The structure of methylated xanthines in relation to their effects on DNA synthesis and cell lethality in nitrogen mustard-treated cells.

The variation in cellular response to alkylated xanthines possessing different side chains has been used to evaluate more fully the effect of caffeine on both survival and DNA synthesis in cells with DNA damage. A correlation is observed between the ability of these xanthines to reverse the inhibitory effects of nitrogen mustard damage on DNA synthesis and their ability to enhance nitrogen mustard lethality in human HT-29 cells. These findings are consistent with our theory that regulation of damaged replicon initiation protects against potentially lethal damage in the form of unrepaired DNA alkylations. Enhancement of nitrogen mustard lethality is observed to have a maximum limit, which can be reduced by highly toxic xanthine concentrations. The lethal effects of xanthines alone at higher concentrations are unrelated to the effects of caffeine specific to nitrogen mustard treated cells, and appear to be related to an immediate reduction in thymidine incorporation most likely caused by inhibition of other enzyme systems influencing DNA synthesis such as de novo and salvage pathways for purine biosynthesis.