INFLUENCE OF AGING ON MULTIORGAN CARCINOGENESIS IN RATS INDUCED BY N-METHYL-N-NITROSOUREA

The effects of aging on the multi-organ carcinogenesis induced in rats by N-methyl-N-nitrosourea (MNU), a direct carcinogen which does not need metabolic activation to exert carcinogenicity, were examined in male F344 rats. In the first experiment, rats at 6, 52, and 98 weeks of age were treated with MNU (20 mg/kg body weight, i.p.) twice weekly for 6 weeks and then maintained without any further treatment for 24 weeks in the case of young and middle-aged rats and for 18 weeks in the case of the old rats. In young rats, malignant lymphomas, particularly thymic types, were observed at significantly high incidence. A striking result in the middle-aged rats was the significantly higher incidence of adenocarcinomas in the small intestine than in young or old animals. The induction of proliferative and neoplastic lesions of the large intestine also tended to be increased in middle-aged rats. In addition, epithelial hyperplasia of the tongue, but not the forestomach, occurred at the highest incidence in the middle-aged group. There were no differences in the induction of epithelial lesions in the urinary bladder among the groups. In a second experiment, investigation of DNA synthesis in the tongue, small and large intestines, urinary bladder and lymph nodes did reveal significant increases or tendency for increase in the MNU-treated groups, but without differences with age. In contrast, the thymus of young rats showed significantly increased incorporation of BrdU label after administration of MNU, whereas it was markedly reduced in middle-aged rats. In a third experiment, O6-methyldeoxyguanine (O6-medG) DNA adduct formation was immunohistochemically detected in various organs including the thymus, forestomach, and small intestine without any differences with age. Thus, the results demonstrated that while the target organs of MNU are modified by the age of the animals, levels of DNA synthesis and O6-medG DNA adduct formation in most cases can not explain the observed differences in carcinogenic susceptibility.