Sequential observations on the occurrence of preneoplastic and neoplastic lesions in mouse colon treated with azoxymethane and dextran sodium sulfate.

Previously, we proposed a novel mouse model for colitis-related colon carcinogenesis using azoxymethane (AOM) and dextran sodium sulfate (DSS) (Cancer Sci 2003; 94: 965-73). In the current study, sequential analysis of pathological alterations during carcinogenesis in our model was conducted to establish the influence of inflammation caused by DSS on colon carcinogenesis in this model. Male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight) and given 2% (w/v) DSS in the drinking water for 7 days, starting 1 week after the AOM injection. They were sequentially sacrificed at weeks 2, 3, 4, 5, 6, 9, 12, and 14 for histopathological and immunohistochemical examinations. Colonic adenomas were found in 2 (40% incidence and 0.40 +/- 0.49 multiplicity) of 5 mice at week 3 and colon carcinomas developed in 2 (40% incidence and 2.00 +/- 3.52 multiplicity) of 5 mice at week 4. Their incidence gradually increased with time and reached 100% (6.20 +/- 2.48 multiplicity) at week 6. At week 14, the multiplicity of adenocarcinoma was 9.75 +/- 2.49 (100% incidence). In addition, colonic dysplasia was noted at all time-points. The scores of colonic inflammation and nitrotyrosine immunohistochemistry were extremely high at early time-points and were well correlated. Our results suggest that combined treatment of mice with AOM and DSS generates neoplasms in the colonic mucosa via dysplastic lesions induced by nitrosative stress.