Repair and replication of DNA containing O6-methylguanine in fetal and adult animal tissues in relation to their susceptibilities to cancer induction by N-nitroso-N-alkylureas.
Experimental evidence and basic concepts support the view that replication of DNA containing the mispairing base O6-alkylguanine is an essential event in the initiation of cancer by simple alkylating agents. The likelihood of induction of cancer in a particular organ would depend on three factors: (1) the initial level of alkylation of DNA in that organ, (2) the rate of removal of O6-alkylguanine from DNA and (3) the extent of DNA replication during the critical period in which O6-alkylguanine is present. In systems in which the initial level of alkylation is approximately uniform in different organs, their relative susceptibilities to cancer would depend on their abilities to remove O6-methylguanine from DNA, and on the rates of replication of DNA after treatment with the carcinogen. To test this concept, repair and replication were studied in tissues with very different susceptibilities to induction of cancer by a low dose of N-methyl-N-nitrosourea, i.e., rat and mouse brain and lung, and rat brain at different stages of fetal and postnatal development. The ability of the tissue to remove O6-methylguanine from DNA was determined by incubation of tissue extracts with extraneously methylated DNA. Replication was studied by measurements of incorporation of 3H-thymidine into DNA. The outstandingly high level of replication of alkylated DNA in mouse thymus correlates with its outstandingly susceptibility to cancer induction by N-methyl-N-nitrosourea (MNU). The result of comparing repair ability and DNA replication in rat and mouse brain and lung suggest that unknown factors are involved in the resistance of the nontarget organs.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001921:Brain / Q000378:metabolism; D002273:Carcinogens; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D005260:Female; D005333:Fetus; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008770:Methylnitrosourea / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism
D002273:Carcinogens; D009607:Nitrosourea Compounds; D006147:Guanine; D008770:Methylnitrosourea; C008449:O-(6)-methylguanine