Importance of DNA repair in the organ specificity of tumour induction by N nitroso carcinogens

The relationship between the incidence of tumors in various organs of the rat after the administration of dimethylnitrosamine (DMN) or diethylnitrosamine (DEN) and the formation and persistence of various alkylated nucleosides in DNA has been studied. Although there is convincing evidence that the metabolic conversion of the nitrosamines into a chemically reactive alkylating species is required for the production of tumors and tumors occur only in those organs capable of metabolizing the nitrosamine, there was no apparent correlation between the amount of alkylation of DNA at the 7 position of guanine and the susceptibility of the tissue to the carcinogenic stimulus. Furthermore, 7 alkylguanine was lost from the DNA of various tissues at approximately the same rate. In contrast, there was a much better correlation between the formation and persistence in DNA of O⁶ alkylguanine and tumor production. For example, after a large dose of DMN which produces kidney tumors but not liver tumors, O⁶ methylguanine was much longer lived in the kidney DNA than in the liver. There was much less difference between the relative stability of this product in the DNA from liver and kidney of rats treated with a low dose of DMN (repeated administration of such doses give rise to liver cancer). These experiments support the hypothesis that the formation and persistence until cell division of certain promutagenic products such as O⁶ alkylguanine might be responsible for the initiation of tumors and that the differing abilities of cells in various organs to catalyze the repair of such products might account for part of the differing susceptibilities of tissues to the nitrosamines. It has been shown that liver extracts are capable of removing O⁶ alkylguanine from DNA in vitro and the properties of this system are being studied in order to evaluate the role of this 'repair system' in the relative insensitivity of the liver to the carcinogenic stimulus provided by the nitrosamines.