TY - JOUR
T1 - A single‐dose protocol for azaserine initiation of pancreatic carcinogenesis in the rat
AU - Yager, James D.
AU - Roebuck, Bill D.
AU - Zurlo, Joanne
AU - Longnecker, Daniel S.
AU - Weselcouch, Edward O.
AU - Wilpone, Seri A.
PY - 1981/11/15
Y1 - 1981/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0019409689&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0019409689&partnerID=8YFLogxK
U2 - 10.1002/ijc.2910280511
DO - 10.1002/ijc.2910280511
M3 - Article
C2 - 6975760
AN - SCOPUS:0019409689
SN - 0020-7136
VL - 28
SP - 601
EP - 606
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 5
ER -