Chemopreventative effect of a cyclooxygenase-2-specific inhibitor (etodolac) on chemically induced biliary carcinogenesis in hamsters.
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 wt. BOP administration was started 4 weeks after surgery, and continued for 18 weeks. The animals were simultaneously orally administered etodolac three times per week at a dose of 10 mg/kg body wt in 0.5% methylcellose solution (etodolac group). The control hamsters were administered methylcellose solution alone. The hamsters were killed 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 six 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. The cell kinetic study demonstrated that the proliferating cell nuclear antigen-labeling index 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 E(2) (PGE(2)) products in the liver tissue were 14.14 +/- 3.31 pg/total protein (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.
Tsuneoka
Noritsugu
N
Department of Transplantation and Digestive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. noritugu@xd5.so-net.ne.jp
Tajima
Yoshitsugu
Y
Kitazato
Amane
A
Fukuda
Kenzo
K
Kitajima
Tomoo
T
Kuroki
Tamotsu
T
Onizuka
Shinya
S
Kanematsu
Takashi
T
D000818:Animals; D001661:Biliary Tract Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002277:Carcinoma / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002768:Choledochostomy / Q000379:methods; D006224:Cricetinae; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D017308:Etodolac / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008647:Mesocricetus; D009602:Nitrosamines / Q000633:toxicity; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D009602:Nitrosamines; D017308:Etodolac; C013622:nitrosobis(2-oxopropyl)amine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone