Experimental Colonic Carcinogenesis: The Interaction of Diet, Bile Acids, Colonic Kallikrein Activity and Colonic Prostaglandin Content

1. Colorectal cancer is currently the fourth most common killing malignancy. There is good epidemiological and experimental evidence that the incidence of this tumour reflects the nature of the diet consumed. Principally, this evidence suggests that a diet which is relatively high in fat or low in dietary fibre content will increase the likelihood of the development of colorectal cancer. 2. Epidemiological and experimental evidence have also demonstrated that the development of colorectal neoplasia is related to the presence of high concentrations of bile acids and their metabolites in the faeces. The concentration of the faecal constituents are dependent on the diet. 3. At the cellular level there are a large number of substances which may control growth and differentation - the autacoids. The kinins and prostaglandins are autacoids which have been shown to have significant effects on the structure and metabolism of the colonic epithelium. 4. There is an established animal model for colonic carcinogenesis whichgives a fair representation of the human condition. 5. This study has examined such an animal model for colorectal carcinogenesis to establish if there is any detectable relationship between the diet, the faecal constituents and the levels of autacoids in the colonic tissue. 6. Furthermore, this study has examined if there are changes in the concentration of autacoids with the development of tumours in the animal model and if the tumour incidence can be altered by pharmacological manipulation of the autacoid activity. 7.575 male albino Swiss rats were entered into the study and 555 survived until completion. These animals were fed one of three diets which were either a) high fat, low fibre; b) low fat, high fibre or c) their standard laboratory diet from entry into the study until completion. 8. In addition, some animals received the carcinogen azoxymethane by weekly, subcutaneous injection over a period of twelve weeks. Selected animals also received daily injections of aprotinin which is a protease inhibitor blocking the formation of kinins. Other animals received indomethacin continuously in their drinking water to inhibit prostaglandin synthesis. Appropriate control treatments were also administered to other animals. 9. Animals were sacrificed at 4, 16 and 24 weeks after entry into the experiment. Samples of colonic tissue were taken to measure: a) the tissue kallikrein-like amidase activity which indicates the kinin-forming activity of the tissue. b) the tissue prostaglandin E2 content since this is the most abundant prostanoid in the colon. c) the crypt cell production rate. 10. Samples of all tumours were assessed histologically and samples of the faeces were taken for bile acid analysis. 11. The animals grew and developed normally on all three diets but those receiving the low fat, high fibre diet gained least weight over the experimental period. Administration of the carcinogen was associated with a reduction in overall weight gain but none of the other drug treatments significantly affected the growth of the animals. 12. Tissue kailikrein-like amidase activity was demonstrated to be present in the rat colon in a distinct pattern with the levels in the caecum being three to five times higher than those elsewhere in the colon. 13. The colonic tissue kailikrein-like amidase activity was unaffected by the diet which the animals consumed and by the use of carcinogen. 14. Regular injections of aprotinin resulted in a significant decrease in the colonic tissue kallikrein-like amidase activity but none of the other treatments had a significant effect on this activity. 15. Prostaglandin E2 was demonstrated to be present in the rat colon in a distinct pattern with the levels in the distal areas of the colon being higher than those in the caecum. 16. The colonic prostaglandin E2 content was unaffected by the diet which the animals consumed but animals receiving the carcinogen had increased levels of prostaglandin E2 in the colon. 17. The regular administration of indomethacin resulted in a significant reduction in the colonic content of prostaglandin E2 but none of the other treatments had a significant effect on the Prostaglandin E2 content. 18. Only animals which received the carcinogen developed tumours of the colorectum. No relationship was seen between the development of tumours and the levels of either tissue kailikrein-like amidase activity or prostaglandin E2. 19. Analysis of the crypt cell production rates by a stathmokinetic method failed to demonstrate any effect of diet on the crypt cell turnover. Aprotinin and indomethacin were both associated with reductions in the crypt cell production rate but use of the carcinogen and tumour development was without effect. 20. The faecal bile acids, neutral sterols and free fatty acids were seen to be significantly related to the diet which the animals consumed