title: Multiple polyps and colonic neoplasia : an experimental model
Creators: name: Carachi, Robert
Publisher: name: University of Glasgow
Year: 1983

description: Colorectal cancer is one of the commonest forms of malignant disease in man. The crude death rate in Scotland is 71 per 100,000 population and there has been no change in the incidence or the mortality of the disease over the past 20 years (Annual Report Registrar General for Scotland). There is a marked variation in the geographic incidence of colorectal cancer, Scotland having a sevenfold increased incidence than other communities (World Health Statistics Annual). The younger patients who develop the disease may have underlying conditions such as polyposis coli and adenomas of the colon which predispose them to develop colonic dysplasia and neoplasia, in contrast to the majority of those in their late middle age who have no apparent predisposing factors. It is with the former younger group of patients in mind that this thesis is submitted, using an appropriate animal model for colonic dysplasia, in an attempt to answer questions on the aetiology of these tumours. Although animal models have been used to study cancer, they were unsatisfactory models for studying colonic dysplasia and neoplasia. The aim of this thesis is to establish a model with an unstable colonic epithelium for colorectal dysplasia to develop, in order to study the effects of the colonic intraluminal environment on this dysplasia. The experimental model for colorectal cancer described (Martin et al. 1973) was used as a basis for the model and their experiment was repeated (CHAPTER TWO). Colorectal neoplasia were induced by using the carcinogen 1:2 Dimethylhydrazine (DMH) injected at a dose of 15 milligrams per kilogram body weight weekly for 28 weeks. This model was modified by reducing the total carcinogen dose to weekly injections for only 16 weeks which produced colonic dysplasia, less extra colonic tumours and minimal carcinogen toxicity. Focal areas of dysplasia underwent changes to polypoidal cancers after stopping the carcinogen at 16 weeks (CHAPTERS THREE AND FOUR). This formed the basis of the animal model modified for epithelial dysplasia (II) used in the rest of the thesis. The experimental model was used to test the hypothesis that by alteration of the colonic intraluminal environment, in this model for colonic dysplasia, the natural history of the disease could be modified (CHAPTER FIVE) . The effect of a high fibre diet on the experimental model proved that fewer tumours appeared and they developed later than rats on a normal diet. Tumours induced in rats on a high fibre diet were morphologically less aggressive and better differentiated histologically. Dietary fibre appears to be one factor which protects the colonic mucosa in the model from the carcinogen 1:2 Dimethylhydrazine (DMH) (CHAPTER SIX). The next set of experiments carried out on the model was to measure the faecal bile acids which have been reported as co-carcinogenic (Hill 1974). The total faecal bile acid excretion was significantly lower in rats on a high fibre diet receiving carcinogen than those similarly injected but on a normal diet or in control animals. These measurements were carried out at six intervals during the 28 weeks of the experiment (CHAPTER SEVEN). The intestinal transit time was measured in a similar experiment on the model, since intestinal transit time has been reported as an explanation for the regional variation in the incidence of colorectal neoplasia (Burkitt 1971). The experiment showed a significant decrease in the intestinal transit time in the rats on a high fibre diet (CHAPTER EIGHT). The faecal weight and bulk was measured in a similar experiment with rats on a high and low fibre diet. The mean faecal residue in rats on a high fibre diet was significantly greater in weight and volume than those on normal diets whether they received carcinogen or not (CHAPTER NINE). The post mortem findings in this last group of animals showed that rats fed on a high fibre diet were found to have fewer tumours (p&lt;0.01) and less mass of tumour was induced (1.4 grams as opposed to 9.6 grams) than rats fed on normal diet receiving carcinogen (CHAPTER TEN). Finally, as a clinical application, the experimental model for colonic epithelial dysplasia was used to test the value of Polyamines as tumour markers after measuring them in patients with colorectal cancer (CHAPTER ELEVEN). The experimental animal model developed for the purpose of studying colonic neoplasia developing from colonic dysplasia has been proved to be reliable and was used to test the hypothesis that alterations in the colonic intraluminal environment can modify the natural course of the disease in this model. It is hoped that this experimental evidence may be of clinical significance to young patients at risk of developing neoplasia because of their predisposition to colonic dysplasia.