A single-dose protocol for azaserine initiation of pancreatic carcinogenesis in the rat.
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 caused 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.
D000818:Animals; D001377:Azaserine / Q000008:administration & dosage; D002273:Carcinogens; D004247:DNA / Q000096:biosynthesis; D005526:Food, Formulated; D008297:Male; D009374:Neoplasms, Experimental / Q000139:chemically induced; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000139:chemically induced*; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains
D002273:Carcinogens; D001377:Azaserine; D004247:DNA