Carcinogenesis Advance Access published online on June 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn152
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Increased expression of inducible nitric oxide synthase (iNOS) in N-nitrosobis(2-oxopropyl)amine-induced hamster pancreatic carcinogenesis and prevention of cancer development by ONO-1714, an iNOS inhibitor
1 Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
2 Japan Food Research Laboratories, Bunkyo 2-3, Chitose-shi, Hokkaido 066-0052, Japan
3 Minase Research Institute, Ono Pharmaceutical Co. Ltd., 1-1, Sakurai 3-chome, Shimamoto-cho, Mishima-gunn, Osaka 618-8585, Japan
4 To whom correspondence should be addressed. Fax: +81 3 3543 9305. E-mail: mtakahas{at}ncc.go.jp
Elevated protein expression of inducible nitric oxide synthase (iNOS) has been observed in human pancreatic cancers and therefore iNOS may play important roles in pancreatic carcinogenesis. This was examined in the present study, using an experimental model with N-nitrosobis(2-oxopropyl)amine (BOP) treated hamsters. RT-PCR analysis demonstrated iNOS expression in a hamster pancreatic cancer cell line as well as in human pancreatic cancer cell lines. Immunohistochemical analysis revealed increased expression of iNOS protein in atypical hyperplasia and ductal adenocarcinomas of the pancreas in BOP-treated hamsters. In addition, iNOS expression was also observed in macrophages and islet cells in pancreatitic tissue surrounding tumors. In order to assess the role of iNOS expression in carcinogenesis in the pancreas, the effects of ONO-1714 ((1S, 5S, 6R, 7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane), an iNOS inhibitor, on hamster pancreatic ductal carcinogenesis were investigated. Female Syrian golden hamsters were treated with BOP at 10 mg/kg body weight, 4 times for one week, and one week after the last carcinogen treatment, ONO-1714 was administered at doses of 100 and 200 ppm in the diet for 15 weeks. The incidences and multiplicities of atypical hyperplasia and invasive adenocarcinoma, and total adenocarcinomas (non-invasive and invasive adenocarcinomas) in the pancreas were significantly lowered by treatment with 200 ppm ONO-1714. Treatment with 100 ppm ONO-1714 also significantly decreased the multiplicities of invasive and total adenocarcinomas. Moreover, treatment with 200 ppm ONO-1714 reduced the number of BOP-induced cholangiocellular tumors. These results suggest that iNOS plays roles in promoting pancreatic carcinogenesis in both early and late stages in hamsters.
Key Words: pancreatic cancer • iNOS • hamster • BOP • ONO-1714
Received April 9, 2008; revised June 5, 2008; accepted June 9, 2008.