Previously, the induction of pancreatic carcinogenesis in the rat using azaserine has involved a multiple‐dose treatment protocol. The objective of the present study was to determine the effect of multiple azaserine treatments on pancreatic DNA synthesis and to develop a protocol for a single‐dose initiation of pancreatic carcinogenesis by azaserine in the rat. Pancreatic DNA synthesis in young rats, which was determined by measuring the amount of [3H]‐thymidine incorporation into DNA, was found to be elevated at 4.3 weeks of age and to decrease to a baseline level by 6.3 weeks. Treatment of 4‐week‐old rats with azaserine resulted in a dose‐dependent inhibition of [3H]‐thymidine incorporation into both pancreatic and liver DNA. Maximum inhibition was seen at 10 mg/kg body weight. This inhibition was followed by a gradual return of incorporation to normal values over a 48 h period. One week following pretreatment with four weekly injections of azaserine at 30 mg/kg, [3H]‐thymidine incorporation into pancreatic and liver DNA was significantly elevated, suggesting that multiple injection protocols cause enhanced DNA synthesis which could have a co‐carcinogenic and/or promotional effect. Single‐doses of azaserine (10, 30 and 60 mg/kg) given at 7 weeks of age caused the appearance of more atypical acinar cell nodules (AACN) than when given at 5 weeks of age. The most effective dose was 30 mg/kg. Using alkaline elution, we determined that this response was due to the occurrence of more DNA damage in the 7‐week‐old animals. Thus, these results demonstrate a rationale for the use of single‐dose initiation protocols in the pancreas. An effective single‐dose protocol for induction of AACN in azaserine‐treated rats fed semi‐synthetic diet is presented.
ASJC Scopus subject areas
- Cancer Research