Effect of Secretin, Cholecystokinin Octapeptide (CCK-8) and a Somatostatin Analogue on Experimental Pancreatic Carcinogenesis

The incidence of pancreatic cancer has increased throughout the world in the last 60 years such that it is now the fourth leading cause of cancer death in the United Kingdom. The tumour usually presents at an advanced stage and cure is rarely possible. Extensive epidemiological investigations during this century suggest that cigarette smoking is the most consistent aetiological factor in the development of pancreatic cancer. Differences in dietary consumption of meat, fat, fruit and vegetables have also been implicated in altering susceptibility to this tumour; high consumption of fat and protein has been thought to increase risk while consumption of fruit and vegetables has been thought to be protective. It remains unclear how these dietary differences affect the risk of developing pancreatic cancer. One possible mechanism that has been suggested for the effects of protein and fat in this regard has been through their influence on endogenous secretion of gastrointestinal hormones such as secretin and cholecystokinin. The late presentation of pancreatic cancer in man makes investigation of the early stage of the carcinogenic process impossible. Two animal models of pancreatic carcinogenesis have been developed in the last 20 years which have allowed investigators to increase our knowledge of some of the processes which go on in this disease. Azaserine has been shown to induce pancreatic acinar cell tumours in rats whereas the nitrosamine family of chemicals, in particular N- nitrosobis(2-oxopropyl)amine (BOP), induces pancreatic tumours with a ductal or ductular morphology in the Syrian golden hamster. The BOP hamster has generally been accepted as the best model for investigating aspects of pancreatic carcinogenesis. In addition to the fact that the tumour induced in the hamster is morphologically similar to the commonest form of human pancreatic cancer (namely ductal adenocarcinoma), the clinical features in the hamster with advanced disease resemble those seen in man, including a propensity for the tumour to metastasize to the liver and other organs. The BOP hamster model has been used widely to investigate some of the factors which might predispose to the development of pancreatic cancer in man. Given that secretin and cholecystokinin have been implicated in the role of diet in the aetiology of human pancreatic cancer, the effects of these and other gastrointestinal hormones have been investigated in the BOP-hamster model. Cholecystokinin and a number of its analogues and secretin have been reported to increase the incidence and extent of BOP induced pancreatic cancer in hamsters. Somatostatin, a gastrointestinal hormone with numerous, predominantly inhibitory, actions, (and largely because of these inhibitory properties,) has been proposed as a possible treatment for pancreatic cancer in man. The aims of this thesis were to investigate the effects of secretin, an octapeptide analogue of cholecystokinin (CCK-8) and a long-acting somatostatin analogue (SMS 201-995) on BOP induced pancreatic carcinogenesis in the Syrian hamster. The hamster model was successfully established. Intraperitoneal (IP) and subcutaneous (SC) BOP were compared for effect on the pancreas. Lesions seen throughout the 20 weeks study period were as previously reported in the literature for both groups. The degree and extent of pre-malignant and malignant change seemed to be greater after 20 weeks in the SC group compared to the IP group. In the second experiment, CCK-8 and secretin stimulated pancreatic juice output when infused intravenously. Pancreatic juice protein and bicarbonate output were also increased. SMS 201-995 suppressed pancreatic juice output. When infused simultaneously with either secretin or CCK-8, SMS 201-995 was still able to suppress pancreatic juice output. Repeated SC injections of secretin, CCK-8 and SMS 201-995 did not have any effect on pancreatic wet weight or DNA content after one or six weeks of treatment. When administered with the carcinogen BOP, CCK-8 did not seem to influence pancreatic carcinogenesis. Secretin and, surprisingly, SMS 201-995, did seem to promote the development of pre-malignant and malignant pancreatic lesions seen histologically. Given that small doses of SMS 201-995 seem to promote pancreatic carcinogenesis in the hamster model, and given the wide interperson variation seen in man in relation to the pharmacology of many compounds, further investigation into the properties of somatostatin analogues should be undertaken before suggesting that these substances should be used to treat human pancreatic cancer. (Abstract shortened by ProQuest.)