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The role of COX-2 in chemoprevention of colorectal cancer: A friend or an enemy?

  • Published:
Current Colorectal Cancer Reports

Abstract

Despite being one of the most preventable forms of cancer, colorectal cancer is still the second highest cause of cancer-related death in the world. One potential prevention strategy consists of drug intervention, also called chemoprophylaxis. Nonsteroidal anti-inflammatory drugs are one of the more studied groups of drugs in colorectal cancer chemoprevention because both epidemiological and experimental studies have shown that these drugs reduce the risk of developing colonic tumors. Cyclooxygenase-2 (COX-2), an isoform of cyclooxygenase, plays an important role in colorectal carcinogenesis. COX-2 selective inhibitors have been tested in the prevention of recurrent colonic adenomas because these drugs have a better profile in gastrointestinal adverse events than nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and it was thought that they could be a better option in chemoprevention of colorectal cancer. However, recent long-term studies have shown that these agents and probably some NSAIDs have an increased risk of cardiovascular events, which has changed the whole scenario. In this paper, we discuss the rationale and the possible indications for the use of COX-2 inhibitors in colorectal cancer prevention as well as the harmful effects these drugs can have on patients.

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References and Recommended Reading

  1. Ferrandez A, Prescott S, Burt RW: COX-2 and colorectal cancer. Curr Pharm Des 2003, 9:2229–2251.

    Article  PubMed  CAS  Google Scholar 

  2. Gupta RA, DuBois RN: Aspirin, NSAIDS, and colon cancer prevention: mechanisms? Gastroenterology 1998, 114:1095–1098.

    Article  PubMed  CAS  Google Scholar 

  3. Sun Y, Tang XM, Half E, et al.: 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.

    PubMed  CAS  Google Scholar 

  4. Koehne C-H, Dubois RN: COX-2 inhibition and colorectal cancer. Semin Oncol 2004, 31(Suppl 7):12–21.

    Article  PubMed  CAS  Google Scholar 

  5. Bedi A, Pasricha PJ, Akhtar AJ, et al.: Inhibition of apoptosis during development of colorectal cancer. Cancer Res 1995, 55:1811–1816.

    PubMed  CAS  Google Scholar 

  6. Gilla S, Sinicrope FA: Colorectal cancer prevention: is an ounce of prevention worth a pound of cure? Semin Oncol 2005, 32:24–34.

    Article  CAS  Google Scholar 

  7. Tang X, Sun YJ, Half E, et al.: Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosisinducing ligand-induced apoptosis in human colon cancer cells. Cancer Res 2002, 62:4903–4908.

    PubMed  CAS  Google Scholar 

  8. Thun MJ, Namboodiri M, Heath CW Jr: Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991, 325:1593–1596.

    Article  PubMed  CAS  Google Scholar 

  9. Giovannucci E, Rimm EB, Stampfer MJ, et al.: Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 1994, 121:241–246.

    PubMed  CAS  Google Scholar 

  10. Giovannucci E, Egan KM, Hunter DJ, et al.: Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995, 333:609–614.

    Article  PubMed  CAS  Google Scholar 

  11. Sturmer T, Glynn RJ, Lee IM, et al.: Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians’ Health Study. Ann Intern Med 1998, 128:713–720.

    PubMed  CAS  Google Scholar 

  12. Smalley W, Ray WA, Daugherty J, Griffin MR: Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer: a population-based study. Arch Intern Med 1999, 159:161–166.

    Article  PubMed  CAS  Google Scholar 

  13. Chan AT, Giovannucci EL, Schernhammer ES, et al.: A prospective study of aspirin use and the risk for colorectal adenoma. Ann Intern Med 2004, 140:157–166.

    PubMed  CAS  Google Scholar 

  14. Rosenberg L, Palmer JR, Zauber AG, et al.: A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer. J Natl Cancer Inst 1991, 83:355–358.

    Article  PubMed  CAS  Google Scholar 

  15. Suh O, Mettlin C, Petrelli NJ: Aspirin use, cancer, and polyps of the large bowel. Cancer 1993, 72:1171–1177.

    Article  PubMed  CAS  Google Scholar 

  16. Freedman AN, Michalek AM, Weiss HA, et al.: Aspirin use and p53 expression in colorectal cancer. Cancer Detect Prev 1998, 22:213–218.

    Article  PubMed  CAS  Google Scholar 

  17. La Vecchia C, Negri E, Franceschi S, et al.: Aspirin and colorectal cancer. Br J Cancer 1997, 76:675–677.

    PubMed  Google Scholar 

  18. Muscat JE, Stellman SD, Wynder EL: Nonsteroidal anti-inflammatory drugs and colorectal cancer. Cancer 1994, 74:1847–1854.

    Article  PubMed  CAS  Google Scholar 

  19. Peleg II, Lubin MF, Cotsonis GA, et al.: Long-term use of nonsteroidal antiinflammatory drugs and other chemopreventors and risk of subsequent colorectal neoplasia. Dig Dis Sci 1996, 41:1319–1326.

    Article  PubMed  CAS  Google Scholar 

  20. Collet JP, Sharpe C, Belzile E, et al.: Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing. Br J Cancer 1999, 81:62–68.

    Article  PubMed  CAS  Google Scholar 

  21. Peleg II, Maibach HT, Brown SH, Wilcox CM: Aspirin and nonsteroidal anti-inflammatory drug use and the risk of subsequent colorectal cancer. Arch Intern Med 1994, 154:394–399.

    Article  PubMed  CAS  Google Scholar 

  22. Kune GA, Kune S, Watson LF: Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 1988, 48:4399–4404.

    PubMed  CAS  Google Scholar 

  23. Reeves MJ, Newcomb PA, Trentham-Dietz A, et al.: Nonsteroidal anti-inflammatory drug use and protection against colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 1996, 5:955–960.

    PubMed  CAS  Google Scholar 

  24. Langman MJ, Cheng KK, Gilman EA, Lancashire RJ: Effect of anti-inflammatory drugs on overall risk of common cancer: case-control study in general practice research database. BMJ 2000, 320:1642–1646.

    Article  PubMed  CAS  Google Scholar 

  25. Bansal P, Sonnenberg A: Risk factors of colorectal cancer in inflammatory bowel disease. Am J Gastroenterology 1996, 91:44–48.

    CAS  Google Scholar 

  26. Paganini-Hill A, Chao A, Ross RK, Henderson BE: Aspirin use and chronic diseases: a cohort study of the elderly. BMJ 1989, 299:1247–1250.

    Article  PubMed  CAS  Google Scholar 

  27. Gann PH, Manson JE, Glynn RJ, et al.: Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 1993, 85:1220–1224.

    Article  PubMed  CAS  Google Scholar 

  28. Schreinemachers DM, Everson RB: Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994, 5:138–146.

    Article  PubMed  CAS  Google Scholar 

  29. Rosenberg L, Louik C, Shapiro S: Nonsteroidal anti-inflammatory drug use and reduced risk of large bowel carcinoma. Cancer 1998, 82:2326–2333.

    Article  PubMed  CAS  Google Scholar 

  30. García-Rodríguez LA, Huerta-Alvarez C: Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. Epidemiology 2001, 12:88–93.

    Article  PubMed  Google Scholar 

  31. Coogan PF, Rosenberg L, Louik C, et al.: NSAIDs and risk of colorectal cancer according to presence or absence of family history of the disease. Cancer Causes Control 2000, 11:249–255.

    Article  PubMed  CAS  Google Scholar 

  32. Gridley G, McLaughlin JK, Ekbom A, et al.: Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993, 85:307–311.

    Article  PubMed  CAS  Google Scholar 

  33. Cibere J, Sibley J, Haga M: Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997, 40:1580–1586.

    Article  PubMed  CAS  Google Scholar 

  34. Kauppi M, Pukkala E, Isomaki H: Low incidence of colorectal cancer in patients with rheumatoid arthritis. Clin Exp Rheumatol 1996, 14:551–553.

    PubMed  CAS  Google Scholar 

  35. Eberhart CE, Coffey RJ, Radhika A, et al.: Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994, 107:1183–1188.

    PubMed  CAS  Google Scholar 

  36. Hasegawa K, Ichikawa W, Fujita T, et al.: Expression of cyclooxygenase-2 (bdCOX-2) mRNA in human colorectal adenomas. Eur J Cancer 2001, 37:1469–1474.

    Article  PubMed  CAS  Google Scholar 

  37. Tomozawa S, Nagawa H, Tsuno N, et al.: Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522. Br J Cancer 1999, 81:1274–1279.

    Article  PubMed  CAS  Google Scholar 

  38. Rahme E, Barkun AN, Youssef T, Marc B: The cyclooxygenase- 2-selective inhibitors rofecoxib and celecoxib prevent colorectal neoplasia occurrence and recurrence. Gastroenterology 2003, 125:404–412.

    Article  PubMed  CAS  Google Scholar 

  39. Steinbach G, Lynch PM, Phillips RKS, et al.: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000, 342:1946–1952. The first study to show that rofecoxib reduced the number and burden of polyps in FAP patients when compared with placebo.

    Article  PubMed  CAS  Google Scholar 

  40. Higuchi T, Iwama T, Yoshinaga K, et al.: A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin Cancer Res 2003, 9:4756–4760.

    PubMed  CAS  Google Scholar 

  41. Hawk ET, Umar A, Viner JL: Colorectal cancer chemoprevention -an overview of the science. Gastroenterology 2004, 126:1423–1447.

    Article  PubMed  Google Scholar 

  42. Baron JA, Cole BF, Sandler RS, et al.: A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003, 348:891–899.

    Article  PubMed  CAS  Google Scholar 

  43. Sandler RS, Halabi S, Baron JA, 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.

    Article  PubMed  CAS  Google Scholar 

  44. Lin J, Hsiao PW, Chiu TH, Chao JI: Combination of cyclooxygenase-2 inhibitors and oxaliplatin increases the growth inhibition and death in human colon cancer cells. Biochem Pharmacol 2005, 70:658–667.

    Article  PubMed  CAS  Google Scholar 

  45. Becerra CR, Frankel EP, Ashfaq R, Gaynor RB: Increased toxicity and lack of efficacy of rofecoxib in combination with chemotherapy for treatment of metastatic colorectal cancer: a phase II study. Int J Cancer 2003, 105:868–872.

    Article  PubMed  CAS  Google Scholar 

  46. Bombardier C, Laine L, Reicin A, 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. In this trial the authors show that the incidence of GI complications in patients taking rofecoxib is lower than in patients taking traditional NSAIDs. The study also showed a higher incidence of nonfatal myocardial infarction in patients taking rofecoxib when compared with naproxen.

    Article  PubMed  CAS  Google Scholar 

  47. Silverstein FE, Faich G, Goldstein JL, et al.: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000, 284:1247–1255. In this trial the authors show that in patients not taking aspirin, high-dose celecoxib was associated with a lower incidence of GI complications than in patients taking traditional NSAIDs.

    Article  PubMed  CAS  Google Scholar 

  48. Silverstein FE, Graham DY, Senior JR, et al.: Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995, 123:241–249.

    PubMed  CAS  Google Scholar 

  49. Weil J, Langman MJ, Wainwright P, et al.: Peptic ulcer bleeding: accessory risk factors and interactions with nonsteroidal anti-inflammatory drugs. Gut 2000, 46:27–31.

    Article  PubMed  CAS  Google Scholar 

  50. Lanas A, Bajador E, Serrano P, et al.: Nitrovasodilators, lowdose aspirin, nonsteroidal anti-inflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 2000, 343:834–839.

    Article  PubMed  CAS  Google Scholar 

  51. Derry S, Loke YK: Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000, 321:1183–1187.

    Article  PubMed  CAS  Google Scholar 

  52. Lanas A, Perez-Aisa MA, Feu F, et al.: A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol 2005, 100:1685–1693. This is the most recent study showing the mortality associated with NSAID therapy.

    Article  PubMed  CAS  Google Scholar 

  53. Lanas A, Hirschowitz BI: Toxicity of NSAIDs in the stomach and duodenum. Eur J Gastroenterol Hepatol 1999, 11:375–381.

    Article  PubMed  CAS  Google Scholar 

  54. Singh G, Triadafllopoulos G: Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl 1999, 56:18–24.

    PubMed  CAS  Google Scholar 

  55. Laine L, Connors LG, Reicin A, et al.: Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology 2003, 124:288–292. This was the first published study to show that the administration of a selective COX-2 inhibitor (rofecoxib) was associated with a lower incidence of serious gastrointestinal complications compared with naproxen. The data were obtained from a post hoc analysis of the VIGOR trial.

    Article  PubMed  CAS  Google Scholar 

  56. Emery P, Zeidler H, Kvien TK, et al.: Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999, 354:2106–2111.

    Article  PubMed  CAS  Google Scholar 

  57. Schnitzer TJ, Burmester GR, Mysler E, et al.: Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004, 364:665–674. This is the largest outcome trial. The authors show that the incidence of GI complications in patients taking lumiracoxib is lower than in patients taking traditional NSAIDs. The study also showed that the GI benefit of lumiracoxib over traditional NSAIDs is very much reduced in the presence of low-dose aspirin.

    Article  PubMed  CAS  Google Scholar 

  58. Hawkey CJ, Skelly MM: Gastrointestinal safety of selective COX-2 inhibitors. Curr Pharm Des 2002, 8:1077–1089.

    Article  PubMed  CAS  Google Scholar 

  59. Watson DJ, Yu Q, Bolognese JA, et al.: The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis. Curr Med Res Opin 2004, 20:1539–1548.

    Article  PubMed  CAS  Google Scholar 

  60. Moore RA, Derry S, Makinson G, McQuay H: Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports. Arthritis Res Ther 2005, 7:R644-R665.

    Article  PubMed  CAS  Google Scholar 

  61. Hunt RH, Harper S, Watson DJ, et al.: The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events. Am J Gastroenterol 2003, 98:1725–1733.

    Article  PubMed  CAS  Google Scholar 

  62. Goldstein JL, Eisen GM, Agrawal N, et al.: Reduced incidence of upper gastrointestinal ulcer complications with the COX-2 selective inhibitor, valdecoxib. Aliment Pharmacol Ther 2004, 20:527–538.

    Article  PubMed  CAS  Google Scholar 

  63. Rabeneck L, Goldstein JL, Vu A, et al.: Valdecoxib is associated with improved dyspepsia-related health compared with nonspecific NSAIDs in patients with osteoarthritis or rheumatoid arthritis. Am J Gastroenterol 2005, 100:1043–1050.

    Article  PubMed  CAS  Google Scholar 

  64. Mamdani M, Rochon PA, Juurlink DN, et al.: Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 2002, 325:624.

    Article  PubMed  CAS  Google Scholar 

  65. Watson DJ, Harper SE, Zhao P-L, et al.: Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000, 160:2998–3003.

    Article  PubMed  CAS  Google Scholar 

  66. Lanas A, Panes J, Pique JM: Clinical implications of COX-1 and/or COX-2 inhibition for the distal gastrointestinal tract. Curr Pharm Des 2003, 9:2253–2266.

    Article  PubMed  CAS  Google Scholar 

  67. Bjarnason I, Hayllar J, MacPherson AJ, Russell AS: Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993, 104:1832–1847.

    PubMed  CAS  Google Scholar 

  68. Goldstein JL, Eisen GM, Lewis B, et al.: Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol 2005, 3:133–141.

    Article  PubMed  Google Scholar 

  69. Messerli FH, Sichrovsky T: Does the pro-hypertensive effect of cyclooxygenase-2 inhibitors account for the increased risk in cardiovascular disease? Am J Cardiol 2005, 96:872–873.

    Article  PubMed  CAS  Google Scholar 

  70. Bresalier RS, Sandler RS, Quan H, et al.: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005, 352:1092–1102. The first study to demonstrate that rofecoxib increased the risk of cardiovascular events after 18 months of treatment when compared with placebo in a population with a history of colorectal adenomas. Such results led to the withdrawal of rofecoxib from the market.

    Article  PubMed  CAS  Google Scholar 

  71. Braunstein N, Polis A: Report of specific cardiovascular outcomes of the ADVANTAGE trial. Ann Intern Med 2005, 143:158–159.

    PubMed  Google Scholar 

  72. Aisen PS, Schafer KA, Grundman M, et al.: Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003, 289(21):2819–2826.

    Article  PubMed  CAS  Google Scholar 

  73. Solomon SD, McMurray JJ, Pfeffer MA, et al.: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005, 352:1071–1080. This study showed that celecoxib was also dose-dependently (400 mg-800 mg/day) associated with increased risk of vascular occlusive events in patients with a history of colorectal adenomas.

    Article  PubMed  CAS  Google Scholar 

  74. Nussmeier NA, Whelton AA, Brown MT, et al.: Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005, 352:1081–1091.

    Article  PubMed  CAS  Google Scholar 

  75. Hippisley-Cox J, Coupland C: Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005, 330:1366.

    Article  PubMed  CAS  Google Scholar 

  76. Ray WA, Stein CM, Daugherty JR, et al.: COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002, 360:1071–1073.

    Article  PubMed  CAS  Google Scholar 

  77. Graham DJ, Campen D, Hui R, et al.: Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005, 365:475–481.

    PubMed  CAS  Google Scholar 

  78. Solomon DH, Schneeweiss S, Glynn RJ, et al.: Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004, 109:2068–2073.

    Article  PubMed  CAS  Google Scholar 

  79. Howes LG, Krum H: Selective cyclo-oxygenase-2 inhibitors and myocardial infarction: How strong is the link? Drug Saf 2002, 25:829–835.

    Article  PubMed  CAS  Google Scholar 

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  1. Service of Digestive Diseases, University Hospital, C/San Juan Bosco 15, 50009, Zaragoza, Spain

    Angel Lanas MD, DSc

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  1. Angel Ferrández MD, DSc
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Ferrández, A., Lanas, A. The role of COX-2 in chemoprevention of colorectal cancer: A friend or an enemy?. Curr colorectal cancer rep 2, 5–12 (2006). https://doi.org/10.1007/s11888-006-0011-1

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