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Carcinogenesis Advance Access originally published online on May 16, 2007
Carcinogenesis 2007 28(10):2193-2198; doi:10.1093/carcin/bgm114
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Enhanced thyroid carcinogenicity of N-nitrosobis(2-oxopropyl)amine in Otsuka Long-Evans Tokushima Fatty rats, a model of type II diabetes mellitus

Katsuhisa Sakano, Mami Takahashi, Michihiro Mutoh, Naoko Niho, Masami Komiya, Hidetaka Sato1, Takuji Tanaka2, Takashi Sugimura and Keiji Wakabayashi*

Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
1 Japan Food Research Laboratories, Bunkyo 2-3, Chitose-shi, Hokkaido 066-0052, Japan
2 Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchida, Ishikawa 920-0293, Japan

* To whom correspondence should be addressed. Tel: +81 3 3542 2511 ext. 4350; Fax: +81 3 3543 9305, Email: kwakabay{at}gan2.res.ncc.go.jp

Epidemiologic data suggest that diabetes mellitus type II is a risk factor for several types of cancer, including pancreatic, liver, colon and thyroid cancers. In the present study, effects of diabetes/hyperlipidemia on N-nitrosobis(2-oxopropyl)amine (BOP)-induced cancer development were examined in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, model animals for non-insulin-dependent diabetes mellitus and Long-Evans Tokushima Otsuka (LETO) rats, appropriate controls. Males of both strains were given four subcutaneous injections of BOP (10 mg/kg body wt) or saline on alternative days, starting at 5 weeks of age. BOP induced tumors in a variety of tissues, including the thyroid gland, colon, kidney, liver and lung. The highest yields were noted for thyroid tumors, the incidence (P = 0.0182) and multiplicity (P < 0.001) of BOP-induced thyroid cancers with marked fibrosis being significantly higher in OLETF than in LETO rats. Interestingly, anaplastic thyroid carcinomas were observed limited to the BOP-treated OLETF rats. Additionally, a greater incidence and frequency of aberrant crypt foci, putative precursor lesions for colon tumors, was observed in the BOP-treated OLETF group. However, BOP was ineffective at inducing pancreatic ductal tumors. No thyroid, liver, lung or colon tumors were found in the OLETF and LETO rats receiving the vehicle. Significant increases in serum levels of insulin, glucose, phospholipids, triglycerides and total cholesterol were detected in the OLETF rats compared with the LETO rats, regardless of the treatment. Our results indicate that diabetic/hyperlipidemic state can enhance BOP-induced carcinogenesis of the thyroid gland and to a lesser extent the colon in OLETF rats.

Abbreviations: ACF, aberrant crypt foci; BOP, N-nitrosobis(2-oxopropyl)amine; LETO, Long-Evans Tokushima Otsuka; OLETF, Otsuka Long-Evans Tokushima Fatty; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, tetraiodothyronine

Received December 27, 2006; revised April 10, 2007; accepted May 8, 2007.


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