Repair and replication of DNA in rat and mouse tissues in relation to cancer induction by N-nitroso-N-alkyl-ureas.

The high susceptibility of certain organs, for example rat brain, to induction of cancer by N-nitroso-N-alkyl-ureas, has been related to a low ability to remove O6-alkylguanine (O6AG) from DNA. It is therefore reasonable to ask why mouse brain, in which there is also a slow disappearance of O6AG from DNA after treatment with nitroso-alkyl-ureas, is not susceptible and why, in mice, thymus and lung are the main target organs. The explanation of the species difference could lie in the fact that replication of alkylated DNA is an essential event in initiation. If nitroso-alkyl-ureas had a greater inhibitory effect in some organs than in others, replication might be inhibited until after the O6AG had been removed, so preventing replication of DNA while still alkylated. This concept was tested by comparing the effect of N-nitroso-N-methyl-urea (NMU) on incorporation of [3H]TdR into DNA of relevant organs in Wistar rats and C57BL mice, and by determining ability to remove O6AG from DNA by measuring the alkyl acceptor protein (AAP) concentrations in these organs. No evidence was obtained that the AAP content was lower or inhibition of replication was less extensive in the organ of the species more susceptible to carcinogenesis than in the same organ of the less susceptible species.