Journal Article

Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine and dextran sodium sulfate in male ICR mice possess β-<i>catenin</i> gene mutations and increases immunoreactivity for β-catenin, cyclooxygenase-2 and inducible nitric oxide synthase

Takuji Tanaka, Rikako Suzuki, Hiroyuki Kohno, Shigeyuki Sugie, Mami Takahashi and Keiji Wakabayashi

in Carcinogenesis

Volume 26, issue 1, pages 229-238
Published in print January 2005 | ISSN: 0143-3334
Published online January 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh292
Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate in male ICR mice possess β-catenin gene mutations and increases immunoreactivity for β-catenin, cyclooxygenase-2 and inducible nitric oxide synthase

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Heterocyclic amines are known to be important environmental carcinogens in several organs including the colon. The aim of this study was to induce colonic epithelial malignancies within a short-term period and analyze the expression of cycooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and β-catenin, and mutations of β-catenin gene in induced tumors. Male Crj: CD-1 mice were given a single i.g. administration (200 mg/kg body wt) of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) followed by 2% dextran sodium sulfate (DSS) in the drinking water for a week. The expression of β-catenin, COX-2 and iNOS was immunohistochemically assessed in colonic epithelial lesions and the β-catenin gene mutations in colonic adenocarcinomas induced were analyzed by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. At week 16, a high incidence of colonic neoplasms with dysplastic lesions developed in mice that received PhIP and DSS, but only a few developed in those given MeIQx and DSS. Immunohistochemically, the adenocarcinomas induced were all positive for three proteins. All seven adenocarcinomas induced by PhIP and DSS have mutations. The findings suggest that DSS exerts powerful tumor-promoting effects on PhIP-initiated colon carcinogenesis in mice and this mouse model is useful for investigating environment-related colon carcinogenesis within a short-term period.

Keywords: ACF, aberrant crypt foci; AOM, azoxymethane; APC, adenomatous polyposis coli; COX, cyclooxygenase; DSS, dextran sodium sulfate; H&E, hematoxylin and eosin; HCA, heterocyclic amine; iNOS, inducible nitric oxide synthase; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline; MeIQ, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline: PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Journal Article.  6379 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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