In vivo repair of rat intestinal DNA damage by alkylating agents

In an effort to evaluate the possible correlation of the transforming ability of the known colon carcinogens dimethylhydrazine, 3-2'-dimethyl-4-aminobiphenyl, and methylazoxymethanolacetate to damage and repair of DNA, a series of compounds known to react with DNA-nitrogen mustard, methylmethanesulfonate, and mitomycin C--were administered to rats that had been prelabeled with 3H-thymidine. The DNA of crypt and villus of the jejunum and crypt and surface cells of the large bowel were analyzed by ultracentrifugation on an alkaline sucrose gradient. All fractions suffered degradation to such an extent that essentially no undamaged DNA was detectable. This was followed by repair and an increase in size. However, in the surface cells of the colon of animals that had received a carcinogenic insult there was far less rapid repair. Since this is the site where tumors would ultimately arise these data are supportive of the hypothesis that there is a relationship between decreased repair and carcinogenicity. In view of the age related incidence of colon cancer, repair in older animals was evaluated and was found to be less than that seen in the young. Since multiple treatment with the carcinogen dimethylhydrazine is required and there is a long latent period, the effect of this treatment on repair potential was evaluated. Similar to what was seen in the older animals, these treated rats had greatly reduced capacity to repair DNA. All these observations are consistent with the hypothesis that decreased repair of DNA alterations is a concomitant of carcinogenesis.