Dietary fat and colon cancer: variable results in animal models.
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Measurements of RNA and DNA in the rat have been used to identify mucosal hyperplasia in the remaining gut within 48 h of partial intestinal loss. Structural adaptation of the ileum is still present 3 months after jejunal resection, whereas transection of the bowel produces merely transient hyperplasia. A humoral factor can be transmitted between rats linked in vascular parabiosis that is capable of stimulating intestinal cell proliferation. Humoral agents may also explain reduced adaptation of the distal bowel after jejunal bypass as opposed to equivalent resection. Although bile can initiate prompt ileal hyperplasia, the additional presence of pancreatic juice is needed to prolong this effect. Adaptation is controlled by luminal and systemic factors that are closely interlinked. Experimental intestinal carcinogenesis is promoted by proximal enterectomy.
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A total of 130 rats were used in various experiments to prepare a new model for colorectal carcinogenesis. The experiments resulted in the development of a surgical technique that creates a subcutaneous cecal hernia, which allows the direct injection of the promoting substance, human bile from percutaneous biliary drainage, into the bowel of the rat. The method permits a direct, complete, and very easy access of a specific amount of the substance to be tested onto the colonic mucosa. The results have proven to be uniformly effective and easily reproducible and to ensure safe management of the animal.
The present survey deals with requirements the experimental-oncological models used in morphogenetic investigations should meet. Data on ways of inducing tumours of various organs the most suited for such investigations are presented. The available at present literature comprises data on different variants of morphogenesis of tumours; in a number of cases malignant neoplasms can develop against the background of an unchanged structure without previous alterations. Because of a contradictory character of the literature reports on morphogenesis of tumours, further investigations into the morphodynamics of the process of cancerogenesis are needed; at present, this may be successfully implemented if adequate models of the majority of tumour diseases in man are available. These studies are of importance for better understanding of pathogenesis or tumour growth and for ascertaining the concept of precancer changes.
Previous studies identified as putative preneoplastic lesions 1) enzyme-altered foci in sections of methacrylate-embedded colon and 2) aberrant crypts in methylene blue-stained unembedded (whole-mount) colon and established that aberrant crypts embedded in methacrylate had enzyme alterations. We have now studied histochemically demonstrable hexosaminidase activity in unembedded or whole-mount preparations of colons from carcinogen-treated rats. These preparations have revealed two populations of crypts that are enzyme-altered: those that are morphologically altered or aberrant and those that are morphologically normal. Both populations can be quantified rigorously in less than an hour with whole-mount preparations reacted for hexosaminidase. The demonstration of phenotypic characteristics with histochemical techniques in whole-mount preparations should have wide applicability to functional studies in many normal and diseased tissues.
Our previous studies have demonstrated that dietary benzylselenocyanate (BSC) and 1,4-phenylenebis (methylene) selenocyanate (p-XSC); organoselenium compounds, act as potential chemopreventive agents in colon carcinogenesis in F344 rats. As a part of a program aimed to develop less toxic and more effective chemopreventive organoselenium compounds than inorganic selenium and BSC, we evaluated the positional isomers of BSC namely o-, m-, and p-methoxy BSC and dibenzyl diselenide (DDS) for their potential chemopreventive properties using colonic epithelial cell proliferation as an efficacy endpoint. p-XSC and inorganic selenium, which were found to inhibit colon carcinogenesis in earlier preclinical efficacy study, were included as positive controls. Male F344 rats were fed the control diet containing 8 ppm Na2SeO3 or 10 ppm of each o-, m-, and p-methoxy BSC and DDS equivalent to 4.1 ppm Se or 20 ppm p-XSC (10 ppm Se) 2 weeks prior to carcinogen (AOM, 15 mg/kg body wt., once weekly for 2 weeks) administration and during and until 8 weeks after AOM treatment. Vehicle-control animals received an equal volume of normal saline. One hour prior to sacrifice, all animals were injected with bromodeoxyuridine (BrdU, 20 mg/kg body wt.). Administration of o-, m-, and p-methoxy BSC, p-XSC, DDS, and Na2SeO3 resulted in decreased colonic labeling index in animal treated with AOM compared to control diet. Notably, p-XSC and Na2SeO3, which showed previously colon tumor inhibitory activity in preclinical efficacy study, were also effective in the present study. The results of our previous and current studies indicate that structurally modified synthetic organoselenium compounds may have great potential as chemopreventive agents.