De novo replication and repair replication of DNA during diethylnitrosamine-induced carcinogenesis

Abstract

Summary Evidence suggests that replication of damaged DNA is an essential early event in carcinogenesis, i.e. replication must take place before the DNA damage caused by the carcinogen has been repaired. When cancer is induced by feeding a diet containing diethylnitrosamine (DEN), a critical minimum period of feeding is essential for induction of tumors within 9 months. This critical time may be the period necessary for stimulation of de novo replication or for inhibition of repair replication. The concept was tested by studying de novo and repair replication during administration of DEN, using a technique for fractionation of nuclei into replication and non-replicating diploids and tetraploids. [3H]- Thymidine ([3H]TdR) incorporation in vivo into replicating nuclei represented de novo replication, while hydroxyurea (HU)-resistant incorporation into non-replicating nuclei represented repair replication. De novo replication increased to a maximum after approx. 6 weeks feeding, while at approximately the same time repair replication was apparently unaltered, as tested by injection of a high dose of dimethylnitrosamine (DMN). The results therefore support the idea that the critical minimum time of feeding DEN is necessary for the development of restorative hyperplasia, when the increased rate of DNA replication increases the probability of synthesis of DNA taking place before damage caused by reaction with the carcinogen has been repaired.