Carcinogenesis Advance Access published online on October 21, 2004
Carcinogenesis, doi:10.1093/carcin/bgh311
© 2004 by Oxford University Press
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1 Department of Transplantation and Digestive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
* To whom correspondence should be addressed. The present study was designed to evaluate whether etodolac, a cyclooxgenase-2 (COX-2)- specific inhibitor, could prevent chemically induced biliary carcinogenesis in bilioenterostomized hamsters. Syrian golden hamsters were subjected to choledochojejunostomy and then received subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) every 2 weeks at a dose of 10 mg/kg body weight. BOP administration was started 4 weeks after surgery, and continued for 18 weeks. The animals were simultaneously orally administered etodolac 3 times per week at a dose of 10 mg/kg body weight in 0.5% methylcellose solution (etodolac group). The control hamsters were administered methylcellose solution alone. The hamsters were sacrificed 22 weeks after surgery, and the biliary carcinomas were evaluated histologically. The presence and degree of cholangitis and the cell kinetic status of the biliary epithelium were also evaluated with special reference to biliary carcinogenesis. Intrahepatic bile duct carcinomas developed in 15 of 17 (88%) hamsters in the control group, and in only 6 of 18 (33%) hamsters in the etodolac group (p<0.01). The incidence and number of developing biliary carcinomas were well correlated with the degree of cholangitis, and severe cholangitis was evident in the controls. Cell kinetic study demonstrated that the proliferating cell nuclear antigen labeling index (PCNA-LI) of the biliary epithelium was 9.67% and 5.14% in the control and etodolac groups, respectively (p<0.05). The mean levels of prostaglandin E2 (PGE2) products in the liver tissue were 14.14 ± 3.31 pg/TP mg in the control group, and 7.46 ± 2.34 pg/TP mg in the etodolac group (p<0.05). These findings indicated that etodolac reduced both the occurrence of severe cholangitis and the acceleration of biliary epithelial cell kinetics after bilioenterostomy, resulting in the prevention of BOP-induced biliary carcinogenesis in hamsters. In conclusion, COX-2-specific inhibitor (etodolac) may be a possible agent against not only reflux cholangitis, but also biliary carcinoma after bilioenterostomy.
Revised September 10, 2004
Accepted October 10, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Chemopreventative effect of a cyclooxygenase-2-specific inhibitor (etodolac) on chemically induced biliary carcinogenesis in hamsters
Noritsugu Tsuneoka, E-mail: noritugu{at}xd5.so-net.ne.jp
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