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 beta-catenin gene mutations and increases immunoreactivity for beta-catenin, cyclooxygenase-2 and inducible nitric oxide synthase.
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 beta-catenin, and mutations of beta-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 beta-catenin, COX-2 and iNOS was immunohistochemically assessed in colonic epithelial lesions and the beta-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.
The Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan. takutt@kanazawa-med.ac.jp
Takuji
T
Tanaka
Rikako
R
Suzuki
Hiroyuki
H
Kohno
Shigeyuki
S
Sugie
Mami
M
Takahashi
Keiji
K
Wakabayashi
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000633:toxicity; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D007093:Imidazoles / Q000633:toxicity; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D011810:Quinoxalines / Q000633:toxicity; D015183:Restriction Mapping; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin
D000925:Anticoagulants; C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D003598:Cytoskeletal Proteins; D007093:Imidazoles; D011810:Quinoxalines; D015534:Trans-Activators; D051176:beta Catenin; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D016264:Dextran Sulfate; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases