Dose-dependent promoting effect of dextran sodium sulfate on mouse colon carcinogenesis initiated with azoxymethane

Abstract

We previously reported a powerful tumorpromoting ability of dextran sodium sulfate (DSS) in a novel mouse model for colitis-related colon carcinogenesis initiated with azoxymethane (AOM). To determine the dose-dependent influence of DSS in our animal model, male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight), followed by DSS at dose levels of 2, 1, 0.5, 0.25, and 0.1% (w/v) in drinking water for 1 week. All animals were sacrificed at week 14 and histological alterations in their colon and nitrotyrosine immunohistochemistry were examined to evaluate the nitrosative stress. In the mice which received AOM and 2% DSS, the incidences (multiplicity) of colonic tubular adenoma and adenocarcinoma were 75% (1.25±1.26/mouse) and 100% (2.75±2.22/mouse), respectively. Mice given AOM and 1% DSS had 80% incidence of adenoma (1.00±0.71/mouse) and 60% incidence of adenocarcinoma (1.40±2.07/mouse) in the colon. In a mouse treated with AOM and 0.5% DSS, only one colonic adenoma (20% incidence with 0.20±0.45 multiplicity) developed. Higher frequency of high-grade colonic dysplasia was noted in mice given AOM and 2% or 1% DSS when compared with mice treated with AOM and lower doses of DSS. Also, scoring of inflammation and nitrotyrosine immunoreactivity suggested that severe inflammation and nitrosation stress caused by high-doses (2% and 1%) of DSS contribute its tumor-promoting effects in mouse colon carcinogenesis initiated with a low dose of AOM. Thus, our findings indicate that a tumor-promoting effect of DSS was dose-dependent (1% or more) and the effect might occur under the condition of inflammation and nitrosation stress.