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Kinetic changes in mucosal ornithine decarboxylase activity during azoxymethane-induced colonic carcinogenesis in the
Abstract:
In the azoxymethane (AOM)-treated rat model of colonic carcinogenesis, serial injections of the carcinogen lead to the eventual development of colonic tumors. However, the precise nature of carcinogenesis events in this commonly used model is not well defined, and the occurrence of classic initiation and promotion phases after serial injections is uncertain. Since increases in ornithine decarboxylase (ODC) activity have been associated with promotion in other tumor models, we measured mucosal ODC during AOM carcinogenesis in the rat. We gave male Fischer 344 rats ten weekly injections of AOM at a dose of 3 mg/kg (Wk 1-10) and measured colonic mucosal ODC activity during the entire 25-wk course. Colonic tumor incidence at Wk 25 was 0% in controls and 48% in AOM animals (15 of 31). Mucosal ODC in AOM animals was significantly increased over controls. The time course of changes in mucosal ODC was similar throughout the entire colon and differed generally in magnitude only. Distinct and prolonged increases in ODC activity occurred within 4 h of a single injection of carcinogen and persisted for at least 14 days. With a second AOM injection on Day 7, there was another distinct and prolonged increase in ODC over the persistently elevated activity. Over the entire 25 wk, the increase in ODC was distinctly biphasic, higher at Wk 2, 11, and 13 than at Wk 6, 17, 21, and 25. The findings indicate that AOM induces an increase in mucosal ODC during colonic carcinogenesis, and they suggest that this carcinogenesis model, with ten weekly injections of carcinogen, has the properties of a multistep process. The early peak in ODC might be associated with the early carcinogenesis (initiation) phase(s), and a subsequent second increase in ODC might be associated with late carcinogenesis (post-initiation or promotion) phase (s). These results strengthen the utility of the rat AOM colonic carcinogenesis model for further studies of the role of ODC and polyamine metabolism in neoplastic transformation.