Colorectal carcinoma is the second most common cause of cancer deaths in humans yet its pathogenesis is incompletely understood. Chemical induction of human colonic carcinoma is plausible since the intestine represents one of the largest body surfaces that is regularly exposed to carcinogens. A recent report (Carcinogenesis 8:155, 1987) of an enzyme-altered focus in rat colon was confirmed in our laboratory with focal deletions of histochemically demonstrable N-acetyl-beta-D-hexosaminidase and alpha-naphthyl butyrate esterase activities in colonic epithelium of rats treated with dimethylhydrazine (DMH). These focal areas appear to be analogous to the extensively investigated changes in livers of carcinogen-treated rats that have been termed """"""""enzyme-altered"""""""" foci and have been regarded as """"""""putative preneoplastic"""""""" or initiated foci. Altered foci in colonic epithelium of F344 rats, treated with three doses of DMH, will be characterized in serial methacrylate sections for a) 20 histochemical markers, b) their ability to bind lectins, c) their cellular content of DNA, and d) their in vivo labeling indices. Enzyme-altered foci are frequently quantified in 10-15-mum cryostat sections but will now be quantified in 2-4 mum methacrylate sections as adapted by our laboratory (Lab Invest 56: 96, 1987). In addition to demonstration of improved cytologic detail and the preservation of enzymes and antigens, methacrylate greatly facilitates the study of multiple phenotypic alterations in serial sections since 2-micron sections consume relatively little tissue and make many more serial sections possible. Autoradiography with tritiated thymidine will be used to analyze labeling indices; microspectrophotometry, for cellular DNA content. Segments of colon from the same rats will be stained histochemically and examined grossly for the identification of altered foci in situ. Human colons routinely resected for therapeutic purposes will be analyzed for similar altered foci. Dr. Tom Stellato, a surgeon in our center who is interested in colon cancer, does total colonscopy and biopsies rat colons. This will allow future longitudinal studies to test directly the hypotheses that enzyme-altered foci are phenotypically stable and can progress to cancer. Well characterized altered foci in rat colons will allow the future study of """"""""chemopreventive"""""""" agents that might cause foci to regress; effects of dietary constituents on the induction, regression, or progression of foci; effects of immunological manipulation on the progression of foci; and the biochemistry of preneoplasia, especially as it might be exploited in the design of """"""""chemopreventive"""""""" agents.
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