CHOLECYSTOKININ EFFECT ON PANCREATIC GROWTH & TUMORS

胆囊收缩素对胰腺生长的影响

基本信息

批准号：
3187596
负责人：
THOMAS E ADRIAN
金额：
$ 17.22万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-05-01 至 1993-10-31
项目状态：
已结题

项目摘要

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.

用胰蛋白酶抑制剂喂养各种动物会导致显着的胰腺肥大和增生，使动物易感当受到致癌物质的挑战时，会导致肿瘤的发展。生大豆，含有热不稳定胰蛋白酶抑制剂已被证明可以促进自发性肿瘤，在长期研究中。我们之前已经证明了喂食生大豆后大鼠的胰腺生长是伴随着血浆胆囊收缩素（CCK）的升高。 CCK输注时间模仿这种反应的剂量会导致类似的胰腺生长。更多的最近我们已经证明，喂养引起的胰腺生长生大豆粉或仓鼠的高脂肪饮食都被有效且特异性的 CCK 受体拮抗剂。膳食脂肪具有强大的作用 CK 的释放者和人类胰腺癌发病率的增加是据认为与高脂肪摄入有关，因此 CCK 可能是一个贡献因素因素。此外，胰腺肿瘤细胞具有这种受体营养激素。我们假设 CCK 受体阻断将逆转增强作用生大豆或高脂肪饮食对仓鼠胰腺癌的影响即使在喂养的动物中，它也会减少致癌物质的影响正常饮食。目的研究将首先研究CCK受体的作用封锁（L364,718）对生大豆和高脂肪饮食的促进作用化学致癌物（BOP）诱发仓鼠癌的研究。因为初步研究表明大肠和小肠都有生长在生大豆和高脂肪喂养之后，我们将调查营养激素的释放、组织生长和 CCK 受体阻断这些领域也是如此。其次，同一拮抗剂对动物致癌作用的影响将评估正常饮食（低脂肪和煮熟的大豆）。第三，我们将研究启动和启动后的机制。通过检查 DNA 烷基化和组织的关键酶来确定致癌作用分别增长。这些研究可能表明脂肪如何导致胰腺癌发生。