The overall goal is to establish a colony of transgenic mice (elastase promoter-SV40-early antigen) and to further characterize this new model for the study of carcinogenesis in the pancreas. Several dietary and hormonal factors have been found to modulate carcinogenesis in the chemically-induced models and we believe that it will be important to see is these factors exert similar influences in the transgenic model. This background is needed in order to allow the model to be used for further study of dietary and hormonal influences on pancreatic carcinogenesis. Founder pairs of mice that are homozygous for the rat elastase promoter-SV40 gene construct (ELSV) will be obtained from the laboratory of Dr. Ralph Brinster. These mice, which will spontaneously develop exocrine pancreatic carcinomas will be bred in the Animal Research Facility of Dartmouth Medical School to maintain breeding stock, to generate carcinomas for further characterization, and to produce mice for studies of factors that influence the development of tumors. Special attention will be directed to the influence of diet and sex hormones. Diets that will be compared include high and low protein, chow and purified diet, and purified diet with added typsin inhibitor. These diets have been shown to affect pancreatic carcinogenesis in rats or hamsters. The mice will be weaned and fed control or special diets until they show evidence of development of pancreatic tumors by morbidity or abdominal enlargement. The development of carcinomas in male and female mice will be carefully compared to determine if the latent period is similar in the two sexes. All animals, both retired breeders, and those involved in dietary studies will be killed by etherization and then autopsied. At autopsy, the major focus will be on the pancreas which will be weighed and either fixed completely or sampled for histologic study and molecular genetic studies of the DNA. One issue in the histogenesis of pancreatic carcinomas in rodents will be addressed by a second, but related approach. The question is whether carcinomas with ductlike morphology can arise in hamsters from transformed acinar cells. A plasmid containing the SV40 genome as well as the ELSV gene construct of Palmiter will be transfected into primary cultures of hamster acinar cell in an effort to generate tumorigeneic cell lines. Such lines will be inoculated into hamsters and nude mice, and the phenotype of any reulting tumors will be examined.
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