Increasing evidence suggests that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer. This observation is supported by results from animal studies that show fewer tumors per animal and fewer animals with tumors after administration of several different NSAIDs. Results from clinical studies with humans consistently support these findings as well. The intervention data in familial adenomatous polyposis patients establishes that the antineoplastic effect may target human adenoma formation. Supportive evidence comes with both aspirin and non-aspirin NSAIDs. Earlier detection of lesions as a result of drug-induced gastrointestinal bleeding does not seem to account for these findings. The molecular mechanism responsible for the chemopreventive action of this class of drugs is not clear. Protection may affect several pathways, with results including cell cycle arrest, induction of apoptosis, and angiogenesis. This review focuses primarily on the potential chemopreventive activity of NSAIDS in sporadic human colon cancer and adenomas and outlines current concepts for the biologic and biochemical mechanisms for this protective effect.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
References and Recommended Reading
Vane JR: History of aspirin and its mechanism of action. Stroke 1990, 21:IV12-IV23.
Vainio H, Morgran G: Aspirin for the second hundred years: new users for an old drug. Pharmacol Toxicol 1997, 81:151–152.
Parkin DM, Pisani P, Ferlay J: Global cancer statistics. CA Cancer J Clin 1999, 49:33–64.
Morson B: The polyp-cancer sequence in the large bowel, Proc. R. Soc. Mes. 1974, 67: 451–457.
Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990, 61:759–767.
Hamilton SR: The molecular genetics of colorectal neoplasia, Gastroenterology. 1993, 105:3–7.
Winawer S.J, Zauber AG, O’Brien MJ, et al.: Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993, 328:901–906.
Marnett LJ: Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 1992, 52:5575–5589.
Giardiello FM, Offerhaus GJA, DuBois RN: The role of nonsteroidal antiinflammatory drugs in colorectal cancer prevention. Eur J Cancer 1995, 31A:1071–1076.
Smalley W, DuBois RN: Colorectal cancer and non steroidal anti-inflammatory drugs. Adv Pharmacol 1997, 39:1–20. This review covers most of the epidemiologic data concerning the role of NSAIDs in cancer prevention and all of the data from clinical trials. It is an excellent comprehensive review.
Kudo T, Narisawa T, Abo: Antitumor activity of indomethacin on methylazoxymethanol-induced large bowel tumors in rats. Jpn J Cancer Res 1980, 71:260–264.
Williams CS, Smalley W, DuBois RN: Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest 1997, 100:1–5. This review focuses on some of the potential mechanisms for the protective effect seen with NSAID use.
Wargovich MJ, Chen CD, Harris C, et al.: Inhibition of aberrant crypt growth by non-steroidal anti-inflammatory agents and differentiation agents in the rat colon. Int J Cancer 1995, 60:515–519.
Rao CV, Rivenson A, Simi B, et al.: Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal antiinflammatory agent. Cancer Res 1995, 55:1464–1472.
Oshima M, Dinchuk JE, Kargman SL, et al.: Suppression of intestinal polyposis in APCd716 knockout mice by inhibition of prostaglandin endoperoxide synthase-2 (COX-2). Cell 1996, 87:803–809.
Waddell WR, Loughry RW: Sulindac for polyposis of the colon. J Surg Oncol 1983, 24:83–87.
Waddell WR, Gasner GF, Cerise EJ, Loughry RW: Sulindac for polyposis of the colon. Am J Surg 1989, 157:175–178.
Waddell WR, Miesfeld RL: Adenomatous polyposis coli, protein kinases, protein tyrosine phosphatase: the effect of sulindac. J. Surg Onc 1995, 58:252–256.
Labayle D, Fischer D Vielh P, et al.: Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 1991, 101:635–639.
Nugent KP, Farmer KC, Spigelman AD, et al.: Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Brit J Surg 1993, 80:1618–1619.
Giardiello FM, Hamilton SR, Krush AJ, et al.: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993, 328:1313–1316.
Spagnesi MT, Tonelli F, Dolara P, et al.: Rectal proliferation and polyp occurrence in patients with familial adenomatous polyposis after sulindac treatment. Gastroenterology 1994, 106:362–366.
DuBois RN, Giardiello FM, Smalley WE: Nonsteroidal anti-inflammatory drugs, eicosanoids and colorectal cancer prevention. Gastroenterol Clin North Am 1996, 25:773–791.
Marnett LJ: Aspirin and related nonsteroidal anti-inflammatory drugs as chemopreventive agents against colon cancer. Prev Med 1995, 24:103–106.
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.
Sturmer T, Glynn RJ, Lee IM, et al.: Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians’ Health Study. Ann Int Med 1998, 128:713–720.
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.
Smalley W, Ray WA, Daugherty J, Griffin MR: Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer: a population-based study. Arch Int Med 1999, 159:161–169. The association between the use of non-aspirin NSAIDS and reduced risk for CRC is reported in this article. It is an important addition to the literature because of the authors’ description of a clear role for NSAIDs as a class of drugs and their insight that the protective effect is not related to use of aspirin alone.
Kune KA, 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.
Muscat JE, Wynder EL: Anti-inflammatory drugs and rheumatoid arthritis. J Natl Cancer Inst 1993, 85:921–922.
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.
Reeves MJ, Newcomb PA, Trenthamdietz A, et al.: Nonsteroidal anti-inflammatory drug use and protection against colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 1996, 5:955–960.
Suh O, Mettlin C, Petrelli NJ: Aspirin use, cancer, and polyps of the large bowel. Cancer 1993, 72:1171–1177.
Rosenberg L, Palmer J, Zauber A, et al.: A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer. J Natl Cancer Inst 1991, 83:355–358.
Muller AD, Sonnenberg A, Wasserman IH: Diseases preceding colon cancer: a case-control study among veterans. Dig Dis Sci 1994, 39:2480–2484.
Peleg II, Maibach HT, Brown SH, Wilcox CM: Aspirin and nonsteroidal anti-inflammatory drug use and the risk of subsequent colorectal cancer. Arch Int Med 1994, 154:394–399.
Thun MJ, Namboodiri MM, Heath CWJ: Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991, 325:1593–1596.
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.
Rosenberg L, Louik C, Shapiro S: Nonsteroidal antiinflammatory drug use and reduced risk of large bowel carcinoma. Cancer 1998, 82:2326–2333.
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.
Schreinemachers DM, Everson RB: Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994, 5:138–146.
Cibere J, Sibley J, Haga M: Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997, 40:1580–1586.
Kauppi M, Pukkala E, Isomaki H: Low incidence of colorectal cancer in patients with rheumatoid arthritis. Clin Exp Rheumatol 1996, 14:551–553.
Gridley G, McLaughlin JK, Ekbom A, et al.: Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993, 85:307–311.
Schreinemachers DM, Everson RB: Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994, 5:138–146.
Martinez ME, McPherson RS, Levin B, Annegers JF: Aspirin and other nonsteroidal anti-inflammatory drugs and risk of colorectal adenomatous polyps among endoscoped individuals. Cancer Epidemiol Biomarkers Prev 1995, 4:703–707.
Sandler R S, Galanko JC, Murray SC, et al.: Aspirin and nonsteroidal anti-inflammatory agents and risk for colorectal adenomas. Gastroenterology 1998, 114:441–447. Report indicating that the protective effect of NSAIDS is also seen in reduction of colorectal ademonas, which are premalignant lesions.
Logan RF, Little J, Hawkin PG, et al.: Effect of aspirin and non-steroidal anti-inflammatory drugs on colorectal adenomas: case-control study of subjects participating in the Nottingham faecal occult blood screening programme. BMJ 1993, 307: 285–289.
Greenberg ER, Baron JA, Freeman DHJ, et al.: Reduced risk of large-bowel adenomas among aspirin users: the Polyp Prevention Study Group. J Natl Cancer Inst 1993, 85:912–916.
DuBois RN: Nonsteroidal anti-inflammatory drug use and sporadic colorectal adenomas. Gastroenterology 1995, 108:1310–1314.
Landenheim J, Garcia G, Titzer D, et al.: Effect of sulindac on sporadic colonic polyps. Gastroenterology 1995, 108:1083–1087.
Hixson LJ, Earnest DL, Fennerty MB, Sampliner RE: NSAID effect on sporadic colon polyps. Am J Gastroenterol 1993, 88:1652–1656.
DiSario JA, Alberts DS, Tietze CC, et al.: Sulindac induces regression and prevents progression of sporadic colorectal adenomas [abstract]. Gastroenterology 1997, 112:A555.
Muscat JE, Stellman SD, Wynder EL: Nonsteroidal antiinflammatory drugs and colorectal cancer. Cancer 1994, 74:1847–1854.
Hixson LJ, Alberts DS, Krutzsch M, et al.: Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells. Cancer Epidemiol Biomarkers Prev 1994, 3:433–438.
Alberts DS, Hixson L, Ahnen D, et al.: Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase? J Cellular Biochem 1995, 22(suppl):18–23.
Shiff SJ, Qiao L, Tsai LL, Rigas B: Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells. J Clin Invest 1995, 96:491–503.
Chan TA, Morin PJ, Vogelstein B, Kinzler KW: Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci U S A, 1998, 95:681–686.
Taketo, M. M. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 1998, 90:1609–1620. Excellent review on preclinical studies showing a role for Cox-2 in tumorigenesis.
Taketo MM: Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 1998, 90:1529–1536.
Meade EA, Smith WL, DeWitt DL: Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal antiinflammatory drugs. J Biol Chem 1993, 268:6610–6614.
Eberhart CE, DuBois RN: Eicosanoids and the gastrointestinal tract. Gastroenterology 1995, 109:285–301.
Kargman S, O’Neill G, Vickers P, et al.: Expression of prostaglandin G/H synthase-1 and-2 protein in human colon cancer. Cancer Res 1995, 55:2556–2559.
Heath CW Jr, Thun MJ, Greenberg ER, et al.: Nonsteroidal antiinflammatory drugs and human cancer: report of an interdisciplinary research workshop. Cancer 1994, 74:2885–2888.
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.
Garay CA, Engstrom PF: Chemoprevention of colorectal cancer: dietary and pharmacologic approaches. Oncology 1999, 13:89–97.
Sano H, Kawahito Y, Wilder RL, et al.: Expression of cyclooxygenase- 1 and -2 in human colorectal cancer. Cancer Res 1995, 55:3785–3789.
Arber N, Han EK, Sgambato A, et al.: A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes. Gastroenterology 1997, 113:1892–1900.
DuBois RN, Awad J, Morrow, J, et al.: Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-a and phorbol ester. J Clin Invest 1994, 93:493–498.
Shiff SJ, Koutsos MI, Qiao L, Rigas B: Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: effects on cell cycle and apoptosis. Exp Cell Res 1996, 222:179–188.
Piazza GA, Rahm AL, Krutzsch M, et al.: Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995, 55:3110–3116.
Piazza GA, Rahm AK, Finn TS, et al.: Apoptosis primarily accounts for the growth-inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res 1997, 57:2452–2459.
Sheng H, Shao J, Morrow J, et al.: Modulation of apoptosis by prostaglandin treatment in human colon cancer cells. Cancer Res 1998, 58:362–366.
Sheng H, Shao J, Kirkland SC, et al.: Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 1997, 99:2254–2259.
Fukutake M, Nakatsugi S, Isoi T, et al.: Suppressive effects of nimesulide, a selective inhibitor of cyclooxygenase-2, on azoxymethane-induced colon carcinogenesis in mice. Carcinogenesis 1998, 19:1939–1942.
Pasricha PJ, Bedi A, O’Connor K, et al.: The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis. Gastroenterology 1995, 109:994–998.
Tsioulias G, Godwin TA, Goldstein MF, et al.: Loss of colonic HLA antigens in familial adenomatous polyposis. Cancer Res 1992, 52:3449–3452.
Tsioulias GJ, Triadafilopoulos G, Goldin E, et al.:. Expression of HLA class I antigens in sporadic adenomas and histologically normal mucosa of the colon. Cancer Res 1993, 53:2374–2378.
Shiff SJ, Rigas B: Nonsteroidal anti-inflammatory drugs and colorectal cancer: evolving concepts of their chemopreventive actions. Gastroenterology 1997, 113:1992–1993.
Tsujii M, Kawano S, Tsuji S, et al.: Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998, 93:705–716.
Tsujii M, DuBois RN: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase-2. Cell 1995, 83:493–501.
Reddy BS, Rao CV, Seibert K: Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis. Cancer Res 1996, 56:4566–4569.
Singh J, Hamid R, Reddy BS: Dietary fat and colon cancer: modulation of cyclooxygenase-2 by types and amount of dietary fat during the postinitiation stage of colon carcinogenesis, Cancer Res 1997, 57:3465–3470.
About this article
Cite this article
Arber, N., DuBois, R.N. Nonsteroidal anti-inflammatory drugs and prevention of colorectal cancer. Curr Gastroenterol Rep 1, 441–448 (1999). https://doi.org/10.1007/s11894-999-0027-1