Carcinoma of the colon or rectum represents one of the most common malignancies worldwide with a higher prevalence in industrialized regions. Epidemiologic studies of individuals taking non-steroidal anti-inflammatory drugs (NSAIDs) have shown a significant reduction in colorectal cancer (CRC) mortality compared to those individuals not receiving these agents. NSAIDs inhibit the enzymatic activity of both isoforms of cyclooxygenase (COX-1 and COX-2), while COX-2-selective inhibitors have shown some efficacy in reducing polyp formation. COX-2-derived bioactive lipids, including the primary prostaglandin (PG) generated in colorectal tumors, PGE2, are known to stimulate cell migration, proliferation and tumor-associated neovascularization while inhibiting cell death. Here we briefly review the role of NSAIDs in preventing CRC, as well as the proposed mechanism by which a COX-2-derived PG, PGE2, promotes colon cancer.

Keywords:
Colorectal cancer, Cyclooxygenase 2, 15-Hydroxyprostaglandin dehydrogenase, Prostaglandin E2
1.
Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics, 2000. CA Cancer J Clin 2000;50:7–33.
2.
Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971;231:232–235.
3.
DuBois RN, Giardiello FM, Smalley WE: Nonsteroidal anti-inflammatory drugs, eicosanoids and colorectal cancer prevention. Gastroenterol Clin North Am 1996;25:773–791.
4.
Pollard M, Luckert PH: Prevention and treatment of primary intestinal tumors in rats by piroxicam. Cancer Res 1989;49:6471–6473.
5.
Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, et al: A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883–890.
6.
Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, et al: A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891–899.
7.
Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340:1888–1899.
8.
Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, et al: A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 1999;117:776–783.
9.
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520–1528.
10.
Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, et al: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946–1952.
11.
Hernandez MR, Tonda R, Pino M, Serradell M, Arderiu G, Escolar G: Evaluation of effects of rofecoxib on platelet function in an in vitro model of thrombosis with circulating human blood. Eur J Clin Invest 2004;34:297–302.
12.
Brinker A, Goldkind L, Bonnel R, Beitz J: Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib, celecoxib, nabumetone and oxaprozin. Drugs Aging 2004;21:479–484.
13.
Smith WL, DeWitt DL, Garavito RM: Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 2000;69:145–182.
14.
DuBois RN, Abramson SB, Crofford L,Gupta RA, Simon LS, Van De Putte LB: Cyclooxygenase in biology and disease. FASEB J 1998;12:1063–1073.
15.
Tai HH, Ensor CM, Tong M, Zhou H, Yan F: Prostaglandin catabolizing enzymes. Prostaglandins Other Lipid Mediat 2002;68–69:483–493.
16.
Rigas B, Goldman IS, Levine L: Altered eicosanoid levels in human colon cancer. J Lab Clin Med 1993;122:518–523.
17.
Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN: Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183–1188.
18.
Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, et al: Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996;87:803–809.
19.
Liu HL, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, et al: Over-expression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001;276:18563–18569.
20.
Neufang G, Furstenberger G, Heidt M, Marks F, Muller-Decker K: Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin. Proc Natl Acad Sci USA 2001;98:7629–7634.
21.
Quidville V, Segond N, Pidoux E, Cohen R, Jullienne A, Lausson S: Tumor growth inhibition by indomethacin in a mouse model of human medullary thyroid cancer: implication of cyclooxygenases and 15-hydroxyprostaglandin dehydrogenase. Endocrinology 2004;145:2561–2571.
22.
Gee JR, Montoya RG, Khaled HM, Sabichi AL, Grossman HB: Cytokeratin 20, AN43, PGDH, and COX-2 expression in transitional and squamous cell carcinoma of the bladder. Urol Oncol 2003;21:266–270.
23.
Backlund MG, Mann JR, Holla VR, Buchanan FG, Tai HH, Musiek ES, Milne GL, Katkuri S, DuBois RN: 15-Hydroxyprostaglandin dehydrogenase is downregulated in colorectal cancer. J Biol Chem 2004;280:3217–3223.
24.
Turini ME, DuBois RN: Cyclooxygenase-2: a therapeutic target. Annu Rev Med 2002;53:35–57.
25.
Watanabe K, Kawamori T, Nakatsugi S, Ohta T, Ohuchida S, Yamamoto H, et al: Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res 1999;59:5093–5096.
26.
Mutoh M, Watanabe K, Kitamura T, Shoji Y, Takahashi M, Kawamori T, et al: Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res 2002;62:28–32.
27.
Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, et al: Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat Med 2001;7:1048–1051.
28.
Hansen-Petrik MB, McEntee MF, Jull B, Shi H, Zemel MB, Whelan J: Prostaglandin E2 protects intestinal tumors from nonsteroidal anti-inflammatory drug-induced regression in Apc(Min/+) mice. Cancer Res 2002;62:403–408.
29.
Kawamori T, Uchiya N, Sugimura T, Wakabayashi K: Enhancement of colon carcinogenesis by prostaglandin E2 administration. Carcinogenesis 2003;24:985–990.
30.
Wang D, Wang H, Shi Q, Katkuri S, Walhi W, Desvergne B, et al: Prostaglandin E2 promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta. Cancer Cell 2004;6:285–295.
© 2005 S. Karger AG, Basel
2005
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.