Feeding a variety of animals with trypsin inhibitors results in a marked hypertrophy and hyperplasia of the pancreas, which predisposes the animals to the development of tumors when challenged with carcinogens. Raw soya, which contains a heat labile trypsin inhibitor has been shown to promote spontaneous tumors, in long-term studies. We have previously shown that the pancreatic growth in response to feeding raw soya in the rat is accompanied by a rise in plasma cholecystokinin (CCK). Infusion of CCK at a dose which mimics this response causes similar pancreatic growth. More recently we have shown that the pancreatic growth resulting from feeding of either raw soya flour or a high fat diet in the hamster is blocked by a potent and specific CCK receptor antagonist. Dietary fat is a potent releaser of CK and the increasing incidence of pancreatic cancer in man is thought to be related to high fat intake, so CCK could be a contributing factor. In addition, pancreatic tumor cells have receptors for this trophic hormone. We postulate that CCK receptor blockade will reverse the potentiating effects of raw soya or high fat diets on pancreatic cancer in the hamster and that it will reduce the effect of carcinogens even in animals fed normal diets. The purpose studies will firstly investigate the effect of CCK receptor blockade (L364,718) on the promoting effect of raw soya and high fat diets on chemical carcinogen (BOP) induced carcinoma in the hamster. Because preliminary studies demonstrated growth in the large and small bowel following both raw soya and high fat feeding, we will investigate the release of trophic hormones, tissue growth and CCK receptor blockade in these areas too. Secondly the effect of the same antagonist on carcinogenesis in animals on normal diet (low fat and cooked soya) will be assessed. Thirdly we will examine the mechanism of initiation and post-initiation of carcinogenesis by examining DNA alkylation and the key enzymes of tissue growth, respectively. These studies may show how fat contributes to pancreatic carcinogenesis.
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