Chemoprevention of Pancreatic Carcinogenesis

  • Tomohiko Adachi
  • Yoshitsugu Tajima
  • Tamotsu Kuroki
  • Takehiro Mishima
  • Amane Kitasato
  • Noritsugu Tsuneoka
  • Takashi Kanematsu

The present study was designed to establish if Etodolac, a selective cyclooxygenase-2 inhibitor, prevents chemically induced intraductal papillary carcinoma (IPC) in the main pancreatic duct of hamsters. Hamsters were subjected to cholecystoduodenostomy with dissection of the distal end of the common duct. Four weeks after surgery, the surviving hamsters were given subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) 10 mg/kg body weight, every 2 weeks, four times. The animals were divided into three groups based on the simultaneous oral intake of a CE-2 pelleted diet, which contained 0% (group CE, n = 30), 0.01% (group ET, n = 21), or 0.04% Etodolac (group ET4, n = 25), respectively. Hamsters were killed for pathological examination 36 weeks after the operation. The incidence of induced pancreatic carcinoma was 93%, 81%, and 72% in groups CE, ET, and ET4, respectively. The pancreatic carcinomas were classified into four histological types: tubular, papillary, and cystic adenocarcinoma, and IPC. The incidence of IPC and the number of IPCs per animal were significantly lower in groups ET4 (36% and 0.48) and ET (48% and 0.62) than in group CE (67% and 1.30). The proliferating cell nuclear antigen labeling indices in the noncancerous epithelial cells of the main pancreatic duct were 2.8% and 6.8% in groups ET4 and ET, respectively; being significantly lower than that in group CE (10.8%). In conclusion, Etodolac inhibited BOP-induced IPC in hamsters. The suppression of epithelial cell proliferation of the main pancreatic duct was considered a possible mechanism of cancer prevention in this hamster model.


Proliferate Cell Nuclear Antigen Pancreatic Carcinoma Main Pancreatic Duct PGE2 Production Pancreatic Carcinogenesis 
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  1. 1.
    Hruban R.H., Takaori K., Klimstra D.S., Adsay N.V., Albores-Saavedra J., Biankin A.V., Biankin S.A., Compton C., Fukushima N., Furukawa T., Goggins M., Kato Y., Kloppel G., Longnecker D.S., Luttges J., Maitra A., Offerhaus G.J., Shimizu M., Yonezawa S. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am. J. Surg. Pathol., 2004 28:977–987.PubMedCrossRefGoogle Scholar
  2. 2.
    Ohhashi K., Murakami Y., Maruyama M., Takekoshi T., Ohta H., Ohhashi I., Takagi K., Kato Y. Four cases of mucous secreting pancreatic cancer. Prog. Dig. Endosc., 1982 20:348–351.Google Scholar
  3. 3.
    Kloppel G., Luttges J. WHO-classification 2000:Exocrine pancreatic tumors. Verh. Dtsch. Ges. Pathol., 2001 85:219–228.PubMedGoogle Scholar
  4. 4.
    Tanaka M., Chari S., Adsay V., Fernandez-del Castillo C., Falconi M., Shimizu M., Yamaguchi K., Yamao K., Matsuno S. International Association of Pancreatology. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006 6:17–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Kokawa A., Kondo H., Gotoda T., Ono H., Saito D., Nakadaira S., Kosuge T., Yoshida S. Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors. Cancer 2001 91:333–338.PubMedCrossRefGoogle Scholar
  6. 6.
    Niijima M., Yamaguchi T., Ishihara T., Hara T., Kato K., Kondo F., Saisho H. Immunohistochemical analysis and in situ hybridization of cyclooxygenase-2 expression in intraductal papillary-mucinous tumors of the pancreas. Cancer 2002 94:1565–1573.PubMedCrossRefGoogle Scholar
  7. 7.
    Aoki T., Nagakawa Y., Tsuchida A., Kasuya K., Kitamura K., Inoue K., Ozawa T., Koyanagi Y., Itoi T. Expression of cyclooxygenase-2 and vascular endothelial growth factor in pancreatic tumors. Oncol. Rep. 2002 9:761–765.PubMedGoogle Scholar
  8. 8.
    Hu P.J., Yu J., Zeng Z.R., Leung W.K., Lin H.L., Tang B.D., Bai A.H., Sung J.J. Chemoprevention of gastric cancer by celecoxib in rats. Gut 2004 53:195–200.PubMedCrossRefGoogle Scholar
  9. 9.
    Ricchi P., Zarrilli R., Di Palma A., Acquaviva A.M. Nonsteroidal anti-inflammatory drugs in colorectal cancer:from prevention to therapy. Br. J. Cancer 2003 88:803–807.PubMedCrossRefGoogle Scholar
  10. 10.
    Adachi T., Tajima Y., Kuroki T., Mishima T., Kitasato A., Fukuda K., Tsutsumi R., Kanematsu T. Bile-reflux into the pancreatic ducts is associated with the development of intraductal papillary carcinoma in hamsters. J. Surg. Res. 2006 136:106–111.PubMedCrossRefGoogle Scholar
  11. 11.
    Takahashi M., Pour P., Althoff J., Donnelly T. The pancreas of the Syrian hamster (Mesocricetus auratua). Lab. Anim. Sci. 1977 27:336.PubMedGoogle Scholar
  12. 12.
    Rinderknecht H., Maset R., Collias K., Carmack C. Pancreatic secretory profiles of protein, digestive, and lysosomal enzymes in Syrian golden hamster. Effect of secretin and cholecysto-kinin. Dig. Dis. Sci. 1983 28:518.Google Scholar
  13. 13.
    Pour PM. Tomioka T. Tumours of the pancreas. IARC. Sci. Publ. 1996 126:149.Google Scholar
  14. 14.
    Eberhart C.E., Coffey R.J., Radhika A., Giardiello F.M., Ferrenbach S., DuBois R.N. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994 107:1183–1188.PubMedGoogle Scholar
  15. 15.
    Ristimaki A., Honkanen N., Jankala H., Sipponen P., Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res. 1997 57:1276–1280.PubMedGoogle Scholar
  16. 16.
    Zimmermann K.C., Sarbia M., Weber A.A., Borchard F., Gabbert H.E., Schror K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res. 1999 59:198–204.PubMedGoogle Scholar
  17. 17.
    Patel S., Chiplunkar S. Role of cyclooxygenase-2 in tumor progression and immune regulation in lung cancer. Indian J. Biochem. Biophys. 2007 44:419–428.PubMedGoogle Scholar
  18. 18.
    Tsujii M., DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells over-expressing prostaglandin endoperoxide synthase 2. Cell 1995 83:493–501.PubMedCrossRefGoogle Scholar
  19. 19.
    Tsujii M., Kawano S., DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc. Natl. Acad. Sci. U. S. A. 1997 94:3336–3340.PubMedCrossRefGoogle Scholar
  20. 20.
    Tsujii M., Kawano S., Tsuji S., Sawaoka H., Hori M., DuBois R.N. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998 93:705–716.PubMedCrossRefGoogle Scholar
  21. 21.
    Molina M.A., Sitja-Arnau M., Lemoine M.G., Frazier M.L., Sinicrope F.A. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines:growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 1999 59:4356–4362.PubMedGoogle Scholar
  22. 22.
    El-Rayes B.F., Ali S., Sarkar F.H., Philip P.A. Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines. Mol. Cancer Ther. 2004 23:1421–1426.Google Scholar
  23. 23.
    Furukawa F., Nishikawa A., Lee I.S., Kanki K., Umemura T., Okazaki K., Kawamori T., Wakabayashi K., Hirose M. A cyclooxygenase-2 inhibitor, nimesulide, inhibits postinitiation phase of N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamsters. Int. J. Cancer 2003 104:269–273.PubMedCrossRefGoogle Scholar
  24. 24.
    Schuller H.M., Zhang L., Weddle D.L., Castonguay A., Walker K., Miller M.S. The cyclooxygenase inhibitor ibuprofen and the FLAP inhibitor MK886 inhibit pancreatic carcinogenesis induced in hamsters by transplacental exposure to ethanol and the tobacco carcinogen NNK. J. Cancer Res. Clin. Oncol. 2002 128:525–532.PubMedCrossRefGoogle Scholar
  25. 25.
    Crowell P.L., Schmidt C.M., Yip-Schneider M.T., Savage J.J., Hertzler D.A. 2nd, Cummings W.O. Cyclooxygenase-2 expression in hamster and human pancreatic neoplasia. Neoplasia 2006 8:437–445.PubMedCrossRefGoogle Scholar
  26. 26.
    Matsubayashi H., Infante J.R., Winter J., Klein A.P., Schulick R., Hruban R., Visvanathan K., Goggins M. Tumor COX-2 expression and prognosis of patients with resectable pancreatic cancer. Cancer Biol. Ther. 2007 6:1569–1575.PubMedCrossRefGoogle Scholar
  27. 27.
    Yip-Schneider M.T., Barnard D.S., Billings S.D., Cheng L., Heilman D.K., Lin A., Marshall S.J., Crowell P.L., Marshall M.S., Sweeney C.J. Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 2000 21:139–146.PubMedCrossRefGoogle Scholar
  28. 28.
    Larsson S.C., Giovannucci E., Bergkvist L., Wolk A. Aspirin and nonsteroidal anti-inflammatory drug use and risk of pancreatic cancer:a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 2006 15:2561–2564.PubMedCrossRefGoogle Scholar
  29. 29.
    El-Rayes B.F., Zalupski M.M., Shields A.F., Ferris A.M., Vaishampayan U., Heilbrun L.K., Venkatramanamoorthy R., Adsay V., Philip P.A. A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer. Invest. New Drugs 2005 23:583–590.PubMedCrossRefGoogle Scholar
  30. 30.
    Oshima M., Dinchuk J.E., Kargman S.L., Oshima H., Hancock B., Kwong E., Trzaskos J.M., Evans J.F., Taketo M.M. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996 87:803–809.PubMedCrossRefGoogle Scholar
  31. 31.
    Maire F., Hammel P., Terris B., Paye F., Scoazec J.Y., Cellier C., Barthet M., O'Toole D., Rufat P., Partensky C., Cuillerier E., Lévy P., Belghiti J., Ruszniewski P. Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma. Gut 2002 51:717–722.PubMedCrossRefGoogle Scholar
  32. 32.
    Sun Y., Tang X.M., Half E., Kuo M.T., Sinicrope F.A. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res. 2002 62:6323–6328.PubMedGoogle Scholar
  33. 33.
    Adachi T, Tajima Y, Kuroki T, Mishima T, Kitasato A, Tsuneoka N, Kanematsu T. Chemopreventive effects of a selective cyclooxygenase-2 inhibitor (etodolac) on chemically induced intraductal papillary carcinoma of the pancreas in hamsters. Carcinogenesis 2008 29:830–833.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Tomohiko Adachi
    • Yoshitsugu Tajima
      • Tamotsu Kuroki
        • Takehiro Mishima
          • Amane Kitasato
            • 1
          • Noritsugu Tsuneoka
            • Takashi Kanematsu
              1. 1.Department of SurgeryNational Hospital Organization Nagasaki Medical CenterNagasakiJapan

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