Evidence of carcinogen-induced replication of partially-repaired DNA in target cells during nitrosamine carcinogenesis

Abstract

Damage and repair of rat kidney DNA, following administration of the renal carcinogens dimethylnitrosamine and diethylnitrosamine, has been analysed by chromatography on benzoylated-DEAE-cellulose. For this purpose, DNA was labelled in vivo by administration of 3 H-thymidine 30 thr after injection of folic acid. After a recovery period of 10 days, single doses of nitrosamines were administered by i.p. injection. Both compounds caused a dose-dependent increase in the proportion of renal DNA bound to benzoylated-DEAE-cellulose due to the presence of single-stranded regions. In the case of dimethylnitrosamine, greatest structural damage of DNA was detected after completion of the alkylation reaction in vivo. The recovery of renal DNA from nitrosamine-induced damage was monitored in a sequential study. With dimethylnitrosamine, a biphasic pattern was recorded, maximal damage to DNA being evident 1 and 4 days after administration of the carcinogen. The increase at 4 days may be attributed to dimethylnitrosamine-induced proliferative activity in the kidney. The data are discussed with reference to the role of replication of cells containing persistent carcinogen-induced damage in this tumour induction system.