Chemoprevention of Biliary Carcinogenesis

  • Noritsugu Tsuneoka
  • Tamotsu Kuroki
  • Tomoo Kitajima
  • Kenzo Fukuda
  • Shinya Onizuka
  • Yoshitsugu Tajima
  • Takashi Kanematsu

This study was conducted to find out if 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 given subcutaneous injections of N-nitrosobis (2-oxopropyl)amine (BOP) 10 mg/kg body weight every 2 weeks. BOP was started 4 weeks after surgery, and continued for 18 weeks. The animals were simultaneously given etodolac 10 mg/kg body weight in 0.5% methylcellulose solution orally three times per week (etodolac group). The control hamsters were administered methylcellulose solution alone. The hamsters were killed 22 weeks after surgery, and the biliary carcinomas were examined 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 (88%) of 17 hamsters in the control group, but in only 6 (33%) of 18 hamsters in the etodolac group (P < 0.01). The incidence and number of developing biliary carcinomas correlated well 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% in the control group and 5.14% in the etodolac group (P < 0.05). The mean levels of prostaglandin E2 (PGE2) 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 inhibited the occurrence of severe cholangitis and the acceleration of biliary epithelial cell kinetics after bilioenterostomy, thereby preventing BOP-induced biliary carcinogenesis in hamsters. In conclusion, the COX-2-specific inhibitor, etodolac, could be used to prevent not only reflux cholangitis, but also biliary carcinoma after bilioenterostomy.


Bile Duct Proliferate Cell Nuclear Antigen Choledochal Cyst Extrahepatic Bile Duct Biliary Epithelium 
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Copyright information

© Springer 2009

Authors and Affiliations

  • Noritsugu Tsuneoka
    • Tamotsu Kuroki
      • Tomoo Kitajima
        • 1
      • Kenzo Fukuda
        • 2
      • Shinya Onizuka
        • 3
      • Yoshitsugu Tajima
        • Takashi Kanematsu
          1. 1.Department of SurgeryNagasaki Municipal HospitalNagasakiJapan
          2. 2.Department of SurgeryMedical Shimada HospitalOgoriJapan
          3. 3.Department of SurgeryNational Hospital Organization Nagasaki Medical CenterNagasakiJapan

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