Sequential changes in colonic mucosal morphology and epithelial proliferation during chemically induced carcinogenesis in rats

The rat model of azoxymethane (AOM) induced colonic carcinogenesis was evaluated for preneoplastic changes in epithelial DNA synthesis and histopathologic characteristics analogous to those observed in human beings at high risk for colonic carcinoma. 10-week-old male Fischer 344 rats were given 10 weekly subcutaneous injections of AOM at a dose of 15 mg/kg. Every 2 weeks after the first carcinogen dose, 5 animals were sacrificed 1 h after an intraperitoneal injection of methyl-³H-thymidine, 0.5 mCi/kg body weight. The experiment was terminated 25 weeks after the first AOM injection. By autoradiography, the labelling index (LI) of the ascending colon (AC) was 8.6 ± 0.5% for AOM-treated animals and 4.7 ± 0.94% for controls (p < 0.05). In the descending colon (DLC) the LI was 10.3 ± 0.9% for AOM-treated animals as compared to 6.8 ± 1.4% for controls (p < 0.01). In the AC the main zone of DNA synthesis shifted from the lower third to the middle third of the crypt in AOM-treated rats, while in the DLC the zone remained in the basal third. No crypt epithelial hyperplasia was found with carcinogen treatment. Crypt elongation, crypt dilatation, and mucosal edema formation were associated with the course of AOM administration and appeared to be toxic effects. In contrast, the mucus content of the cry pt epithelium showed a biphasic decrease over the entire time course of the study. Dysplastic crypts appeared earlier in the AC, however, and the early appearance was associated with persistently elevated labelling indices and shift in the main zone of DNA synthesis. We conclude that in experimental colonic carcinogenesis, preneoplastic changes in cell proliferation (‘stage I’ and ‘stage IT abnormalities) similar to those in human beings at high risk can be observed. Thus, despite the absence of an adenoma-carcinoma sequence, experimental colonic carcinogenesis provides an important model to study modulators of preneoplastic changes and their impact on malignant transformation of colonic mucosa.