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Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595 [T. K., C. V. R., B. S. R.]; and Searle Research and Development. St. Louis, Missouri 63137 [K. S.]
Epidemiological and laboratory studies suggest that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer and that the inhibition of colon carcinogenesis is mediated through modulation of prostaglandin production by cyclooxygenase (COX) isozymes (COX-1 and -2). Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 activity could potentially serve as chemopreventive agents. Our recent study indicated that celecoxib (SC-58635), a specific COX-2 inhibitor, suppressed colonic aberrant crypt foci formation induced by azoxymethane in rats and led us to investigate more specifically the chemopreventive potential of this compound using colon tumors as end points. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or an experimental diet containing 1500 ppm celecoxib. Two weeks later, all animals except those in the saline-treated groups received s.c. injections of azoxymethane (15 mg/kg of body weight) once weekly for 2 weeks. All groups were kept on their regimen until the experiment was terminated, 50 weeks after carcinogen treatment. Colon tumors were evaluated histopathologically. Remarkably, dietary administration of celecoxib inhibited both incidence and multiplicity of colon tumors by about 93 and 97%, respectively. It also suppressed the overall colon tumor burden by more than 87%. The degree of tumor inhibition was more pronounced with celecoxib than it was with previously evaluated nonsteroidal anti-inflammatory drugs. The results of this study provide evidence, for the first time, that a specific COX-2 inhibitor, celecoxib, possesses strong chemopreventive activity against colon carcinogenesis.
1 This work was supported in part by Searle Research and Development (St. Louis, MO).
2 To whom requests for reprints should be addressed, at American Health Foundation, One Dana Road, Valhalla, NY 10595.
Received 11/21/97. Accepted 12/23/97.
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 N. M. Gajraj Cyclooxygenase-2 Inhibitors Anesth. Analg., June 1, 2003; 96(6): 1720 - 1738. [Full Text] [PDF]
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D. E. Corpet and F. Pierre Point: From Animal Models to Prevention of Colon Cancer. Systematic Review of Chemoprevention in Min Mice and Choice of the Model System Cancer Epidemiol. Biomarkers Prev., May 1, 2003; 12(5): 391 - 400. [Abstract] [Full Text] [PDF]
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R. Fukuda, B. Kelly, and G. L. Semenza Vascular Endothelial Growth Factor Gene Expression in Colon Cancer Cells Exposed to Prostaglandin E2 Is Mediated by Hypoxia-inducible Factor 1 Cancer Res., May 1, 2003; 63(9): 2330 - 2334. [Abstract] [Full Text] [PDF]
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T. Kawamori, N. Uchiya, T. Sugimura, and K. Wakabayashi Enhancement of colon carcinogenesis by prostaglandin E2 administration Carcinogenesis, May 1, 2003; 24(5): 985 - 990. [Abstract] [Full Text] [PDF]
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Y. Miyata, S. Koga, S. Kanda, M. Nishikido, T. Hayashi, and H. Kanetake Expression of Cyclooxygenase-2 in Renal Cell Carcinoma: Correlation with Tumor Cell Proliferation, Apoptosis, Angiogenesis, Expression of Matrix Metalloproteinase-2, and Survival Clin. Cancer Res., May 1, 2003; 9(5): 1741 - 1749. [Abstract] [Full Text] [PDF]
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H. A. Minter, J. W. Eveson, S. Huntley, D. J. E. Elder, and A. Hague The Cyclooxygenase 2-selective Inhibitor NS398 Inhibits Proliferation of Oral Carcinoma Cell Lines by Mechanisms Dependent and Independent of Reduced Prostaglandin E2 Synthesis Clin. Cancer Res., May 1, 2003; 9(5): 1885 - 1897. [Abstract] [Full Text] [PDF]
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W.-C. Huang, J.-J. Chen, H. Inoue, and C.-C. Chen Tyrosine Phosphorylation of I-{kappa}B Kinase {alpha}/{beta} by Protein Kinase C-Dependent c-Src Activation Is Involved in TNF-{alpha}-Induced Cyclooxygenase-2 Expression J. Immunol., May 1, 2003; 170(9): 4767 - 4775. [Abstract] [Full Text] [PDF]
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 T. Inaba, H. Sano, Y. Kawahito, T. Hla, K. Akita, M. Toda, I. Yamashina, M. Inoue, and H. Nakada Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells PNAS, March 4, 2003; 100(5): 2736 - 2741. [Abstract] [Full Text] [PDF]
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B. A. Narayanan, N. K. Narayanan, B. Simi, and B. S. Reddy Modulation of Inducible Nitric Oxide Synthase and Related Proinflammatory Genes by the Omega-3 Fatty Acid Docosahexaenoic Acid in Human Colon Cancer Cells Cancer Res., March 1, 2003; 63(5): 972 - 979. [Abstract] [Full Text] [PDF]
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M. Yao, S. Kargman, E. C. Lam, C. R. Kelly, Y. Zheng, P. Luk, E. Kwong, J. F. Evans, and M. M. Wolfe Inhibition of Cyclooxygenase-2 by Rofecoxib Attenuates the Growth and Metastatic Potential of Colorectal Carcinoma in Mice Cancer Res., February 1, 2003; 63(3): 586 - 592. [Abstract] [Full Text] [PDF]
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 K. Takahashi, Y. Saishin, Y. Saishin, K. Mori, A. Ando, S. Yamamoto, Y. Oshima, H. Nambu, M. B. Melia, D. P. Bingaman, et al. Topical Nepafenac Inhibits Ocular Neovascularization Invest. Ophthalmol. Vis. Sci., January 1, 2003; 44(1): 409 - 415. [Abstract] [Full Text] [PDF]
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Y. Yamada, T. Oyama, Y. Hirose, A. Hara, S. Sugie, K. Yoshida, N. Yoshimi, and H. Mori {beta}-Catenin mutation is selected during malignant transformation in colon carcinogenesis Carcinogenesis, January 1, 2003; 24(1): 91 - 97. [Abstract] [Full Text] [PDF]
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Y. Hirose, T. Kuno, Y. Yamada, K. Sakata, M. Katayama, K. Yoshida, Z. Qiao, K. Hata, N. Yoshimi, and H. Mori Azoxymethane-induced beta-catenin-accumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis Carcinogenesis, January 1, 2003; 24(1): 107 - 111. [Abstract] [Full Text] [PDF]
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J. Chu, F. L. Lloyd, O. C. Trifan, B. Knapp, and M. T. Rizzo Potential Involvement of the Cyclooxygenase-2 Pathway in the Regulation of Tumor-associated Angiogenesis and Growth in Pancreatic Cancer Mol. Cancer Ther., January 1, 2003; 2(1): 1 - 7. [Abstract] [Full Text] [PDF]
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R. K. Wali, S. Khare, M. Tretiakova, G. Cohen, L. Nguyen, J. Hart, J. Wang, M. Wen, A. Ramaswamy, L. Joseph, et al. Ursodeoxycholic Acid and F6-D3 Inhibit Aberrant Crypt Proliferation in the Rat Azoxymethane Model of Colon Cancer: Roles of Cyclin D1 and E-Cadherin Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1653 - 1662. [Abstract] [Full Text] [PDF]
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H. J. Lin, K. M. Lakkides, T. O. Keku, S. T. Reddy, A. D. Louie, I. H. Kau, H. Zhou, J. S. Y. Gim, H. L. Ma, C. F. Matthies, et al. Prostaglandin H Synthase 2 Variant (Val511Ala) in African Americans May Reduce the Risk for Colorectal Neoplasia Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1305 - 1315. [Abstract] [Full Text] [PDF]
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Y. Sun, X. M. Tang, E. Half, M. T. Kuo, and F. A. Sinicrope Cyclooxygenase-2 Overexpression Reduces Apoptotic Susceptibility by Inhibiting the Cytochrome c-dependent Apoptotic Pathway in Human Colon Cancer Cells Cancer Res., November 1, 2002; 62(21): 6323 - 6328. [Abstract] [Full Text] [PDF]
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V. A. Patel, M. J. Dunn, and A. Sorokin Regulation of MDR-1 (P-glycoprotein) by Cyclooxygenase-2 J. Biol. Chem., October 4, 2002; 277(41): 38915 - 38920. [Abstract] [Full Text] [PDF]
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L. R. Kisley, B. S. Barrett, L. D. Dwyer-Nield, A. K. Bauer, D. C. Thompson, and A. M. Malkinson Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice Carcinogenesis, October 1, 2002; 23(10): 1653 - 1660. [Abstract] [Full Text] [PDF]
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T. Kitamura, T. Kawamori, N. Uchiya, M. Itoh, T. Noda, M. Matsuura, T. Sugimura, and K. Wakabayashi Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis Carcinogenesis, September 1, 2002; 23(9): 1463 - 1466. [Abstract] [Full Text] [PDF]
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K.-i. Sunayama, H. Konno, T. Nakamura, H. Kashiwabara, T. Shoji, T. Tsuneyoshi, and S. Nakamura The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APC{Delta}474 knockout mice Carcinogenesis, August 1, 2002; 23(8): 1351 - 1359. [Abstract] [Full Text] [PDF]
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R K S Phillips, M H Wallace, P M Lynch, E Hawk, G B Gordon, B P Saunders, N Wakabayashi, Y Shen, S Zimmerman, L Godio, et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis Gut, June 1, 2002; 50(6): 857 - 860. [Abstract] [Full Text] [PDF]
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H. F. Tiano, C. D. Loftin, J. Akunda, C. A. Lee, J. Spalding, A. Sessoms, D. B. Dunson, E. G. Rogan, S. G. Morham, R. C. Smart, et al. Deficiency of Either Cyclooxygenase (COX)-1 or COX-2 Alters Epidermal Differentiation and Reduces Mouse Skin Tumorigenesis Cancer Res., June 1, 2002; 62(12): 3395 - 3401. [Abstract] [Full Text] [PDF]
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J. G. Edwards, S. P. Faux, S. M. Plummer, K. R. Abrams, R. A. Walker, D. A. Waller, and K. J. O'Byrne Cyclooxygenase-2 Expression Is a Novel Prognostic Factor in Malignant Mesothelioma Clin. Cancer Res., June 1, 2002; 8(6): 1857 - 1862. [Abstract] [Full Text] [PDF]
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K. Subbaramaiah, L. Norton, W. Gerald, and A. J. Dannenberg Cyclooxygenase-2 Is Overexpressed in HER-2/neu-positive Breast Cancer. EVIDENCE FOR INVOLVEMENT OF AP-1 AND PEA3 J. Biol. Chem., May 17, 2002; 277(21): 18649 - 18657. [Abstract] [Full Text] [PDF]
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 S. Chu, S. Rushdi, E.T. Zumpe, P. Mamers, D.L. Healy, T. Jobling, H.G. Burger, and P.J. Fuller FSH-regulated gene expression profiles in ovarian tumours and normal ovaries Mol. Hum. Reprod., May 1, 2002; 8(5): 426 - 433. [Abstract] [Full Text] [PDF]
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D. K. Bol, R. B. Rowley, C.-P. Ho, B. Pilz, J. Dell, M. Swerdel, K. Kiguchi, S. Muga, R. Klein, and S. M. Fischer Cyclooxygenase-2 Overexpression in the Skin of Transgenic Mice Results in Suppression of Tumor Development Cancer Res., May 1, 2002; 62(9): 2516 - 2521. [Abstract] [Full Text] [PDF]
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K. Subbaramaiah, P. A. Cole, and A. J. Dannenberg Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms Cancer Res., May 1, 2002; 62(9): 2522 - 2530. [Abstract] [Full Text] [PDF]
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G. Zahner, G. Wolf, M. Ayoub, R. Reinking, U. Panzer, S. J. Shankland, and R. A. K. Stahl Cyclooxygenase-2 Overexpression Inhibits Platelet-derived Growth Factor-induced Mesangial Cell Proliferation through Induction of the Tumor Suppressor Gene p53 and the Cyclin-dependent Kinase Inhibitors p21waf-1/cip-1 and p27kip-1 J. Biol. Chem., March 15, 2002; 277(12): 9763 - 9771. [Abstract] [Full Text] [PDF]
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 J. M. Wallace Nutritional and Botanical Modulation of the Inflammatory Cascade--Eicosanoids, Cyclooxygenases, and Lipoxygenases-- As an Adjunct in Cancer Therapy Integr Cancer Ther, March 1, 2002; 1(1): 7 - 37. [Abstract] [PDF]
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E. Half, X. M. Tang, K. Gwyn, A. Sahin, K. Wathen, and F. A. Sinicrope Cyclooxygenase-2 Expression in Human Breast Cancers and Adjacent Ductal Carcinoma in Situ Cancer Res., March 1, 2002; 62(6): 1676 - 1681. [Abstract] [Full Text] [PDF]
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 C. Denkert, M. Kobel, S. Pest, I. Koch, S. Berger, M. Schwabe, A. Siegert, A. Reles, B. Klosterhalfen, and S. Hauptmann Expression of Cyclooxygenase 2 Is an Independent Prognostic Factor in Human Ovarian Carcinoma Am. J. Pathol., March 1, 2002; 160(3): 893 - 903. [Abstract] [Full Text] [PDF]
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T. Niki, T. Kohno, S. Iba, Y. Moriya, Y. Takahashi, M. Saito, A. Maeshima, T. Yamada, Y. Matsuno, M. Fukayama, et al. Frequent Co-Localization of Cox-2 and Laminin-5 {gamma}2 Chain at the Invasive Front of Early-Stage Lung Adenocarcinomas Am. J. Pathol., March 1, 2002; 160(3): 1129 - 1141. [Abstract] [Full Text] [PDF]
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