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The modifying effect of dietary Peucedanum japonicum (PJ), which is a traditional herb in the Ryukyu Islands and is an anti-oxidant, on azoxymethane (AOM)-induced rat colon carcinogenesis was examined. Male F344 rats were divided into six groups: rats in groups 1-4 were given subcutaneous injection of AOM (20 mg/kg body weight) once a week for 2 weeks. Rats in groups 2, 3 and 4 were fed the diets containing 0.2 and 1% PJ and 0.025% chlorogenic acid, respectively. We observed modification of the preneoplastic lesions of both aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCAC) in colon carcinogenesis, microscopically and immunohistochemically. The numbers of ACF consisting of more than four aberrant crypts per rat in groups 2 (3.2+/-1.7) and 3 (3.0+/-3.2) were significantly lower than that of group 1 (10.8+/-4.9; P<0.05, respectively). The mean number of BCAC in both groups 2 (0.88+/-0.48/cm2/rat) and 3 (0.81+/-0.34/cm2/rat) was significantly lower than that in group 1 (2.13+/-0.54/cm2/rat; P < 0.0001, respectively). In addition, proliferating cell nuclear antigen labeling indices in group 2 (10.98+/-2.03) and group 3 (9.85+/-2.62) were significantly lower than that in group 1 (14.87+/-3.93; P < 0.001 and P < 0.0001, respectively). These findings indicate that PJ inhibits both ACF formation and accumulation of beta-catenin, and that PJ also reduces the cell proliferation activity, suggesting that PJ may have chemopreventive potential for colon carcinogenesis.

The agent N-methyl-N-nitrosourea (MNU) is a direct acting carcinogen and induces well-differentiated adenocarcinoma on the rat gastric mucosa. In this study, 27 histopathologically verified gastric carcinomas induced in male F344 rats were analyzed for mutations in the N-terminal phosphorylation sites (codons 1-51) of the beta-catenin gene by using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) assays. In parallel studies, the specific localization of the beta-catenin protein was also examined by immunohistochemical analysis. No mutations in the beta-catenin gene were found in any of 27 gastric carcinomas induced by MNU. Immunohistochemical analysis resulted in the beta-catenin protein to be localized in the plasma membrane but cytoplasmic and/or nuclear accumulation of beta-catenin was not identified in any of these carcinomas. These results suggest that mutations in the beta-catenin gene are less contributory to the development of rat gastric carcinomas induced by MNU. This animal model may provide a system for evaluating the mechanism of human gastric carcinogenesis that is not associated with beta-catenin gene mutations.

The multiple intestinal neoplasia (min) mouse is a well-established cancer model in which loss of a single copy of the APC protein predisposes mice to the development of numerous tumors in the intestine. We have developed a novel variation of the min mouse model by using azoxymethane (AOM) to cause an increase in tumor incidence, number and size. Thus, treatment of min mice with AOM resulted in 2.6-, 6.3- and 5.9-fold increases in overall tumor incidence, multiplicity and size, respectively, when compared to wild type C57BL/6J mice treated with AOM. Furthermore, adenocarcinomas of the colon, which are otherwise relatively rare in min mice, increased in incidence (P<0.004), multiplicity (P<0.005), and size (P<0.02) in the AOM-treated min mice when compared to control untreated min mice. Of these adenocarcinomas, the number of poorly plus moderately differentiated adenocarcinomas was also significantly higher in the AOM-treated min mice (P<0.008). Thirty-seven histopathologically verified colon tumors (eight adenomas, five carcinoma in situ and 24 adenocarcinomas) induced in min mice and in C57BL/6J mice after treatment with or without AOM were analyzed for mutations in the beta-catenin gene or de novo mutations in the Apc gene. No mutations in the beta-catenin gene were found in any of colon tumors in min mice with or without treatment with AOM. However, mutations in either the beta-catenin gene or the Apc gene were found in tumors induced in C57BL/6J mice by AOM. These results suggest that mutations in the beta-catenin gene are less contributory to tumor development in min mice, as is the case in familial adenomatous polyposis (FAP) in humans. However, de novo mutations in either the Apc or beta-catenin gene can play a role in tumor development in C57BL/6J mice treated with AOM. The differences in mutation status between min and C57BL/6J mice may indicate different genetic pathways for developing colon tumors. These two experimental systems may, therefore, be useful animal models of human colon carcinomas in patients with FAP and in patients with sporadic colon carcinomas.