This is a revised competing continuation proposal to study transplacental pancreatic carcinogenesis induced by coadministration of ethanol and the nitrosamine carcinogen NNK in a hamster model. Pregnant hamsters are administered 10% ethanol in drinking water from day 5 through day 15 of gestation and are then given a single intratracheal dose of 50 mg/kg NNK on day 15. The offspring develop adenocarcinomas of the exocrine pancreas with 50% incidence (males) and 77% incidence (females) as well as pancreatitis and marked acinar and ductular cell hyperplasia. Dr. Schuller proposes to investigate the mechanisms of carcinogenesis in this model. The general hypothesis to be tested appears to be that through a combination of b-adrenergic actions and in situ bioactivation to reactive intermediates, NNK initiates pancreatic tumorigenesis.
The specific aims are: 1) to investigate the role of the b-adrenergic receptor pathway in the initiation and development of pancreatic tumors; 2) to investigate the modulation of NNK metabolism and DNA adduction in fetal liver and pancreas by ethanol, 3) to identify mutations induced in K-ras and p53 genes in hamster pancreatic tumors; 4) to investigate the roles of individual cytochrome P450 enzymes in the bioactivation of NNK in fetal pancreas in vitro and in vivo; and 5) to investigate the ability of the nonsteroidal antiinflammatory agent sulindac to modulate pancreatic carcinogenesis. It is proposed that these studies will serve as the basis for developing effective strategies for prevention of cancer in the children of smokers.
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