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Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics

Key Points

  • Non-steroidal anti-inflammatory drugs (NSAIDs) are effective chemopreventive agents against colorectal neoplasia.

  • NSAID use is associated with a reduced risk of several other types of malignancies, but randomized controlled trials for primary or secondary prevention are still needed.

  • A key mechanism for NSAID efficacy is cyclooxygenase (COX) inhibition and reduced production of prostaglandins.

  • COX2-specific inhibitors (COXibs) might be less toxic to the gastrointestinal tract than NSAIDs that target both COX1 and COX2. However, cardiovascular toxicity associated with COXibs raises concerns.

  • Inherited genetic factors can explain some inter-individual differences in NSAID metabolism and prostaglandin synthesis.

  • Initial epidemiological studies indicate that only in a genetically defined subset of the population will NSAIDs prevent colorectal neoplasia, which suggests pharmacogenetic effects.

  • Pharmacogenetic investigations are expected to help establish the individual risk–benefit ratio for NSAID use and therefore allow tailoring of chemoprevention.

  • In general, a multi-agent, multi-targeted approach to chemoprevention is to be recommended. However, NSAIDs are effective as single agents because they work early in carcinogenesis across multiple pathways.

Abstract

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) show indisputable promise as chemopreventive agents. Possible targets include cancers of the colon, stomach, breast and lung. However, recent studies raise concern about potential cardiovascular toxicity associated with the use of NSAIDs that specifically target the enzyme cyclooxygenase 2. These findings, and others that show that inherited genetic characteristics might determine preventive success, argue for new strategies that are tailored to individual medical history and genetic make-up.

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Figure 1: Inflammation and carcinogenesis.
Figure 2: NSAIDs, COX inhibition and prostaglandins.
Figure 3: NSAIDs and non-COX targets.
Figure 4: NSAID metabolism and excretion.
Figure 5: NSAIDs and pharmacogenetic effects.

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References

  1. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy — I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br. Med. J. 308, 81–106 (1994).

  2. Hussain, S. P., Hofseth, L. J. & Harris, C. C. Radical causes of cancer. Nature Rev. Cancer 3, 276–285 (2003).

    Article  CAS  Google Scholar 

  3. Ohshima, H., Tatemichi, M. & Sawa, T. Chemical basis of inflammation-induced carcinogenesis. Arch. Biochem. Biophys. 417, 3–11 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Giovannucci, E. The prevention of colorectal cancer by aspirin use. Biomed. Pharmacother. 53, 303–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Brown, J. R. & DuBois, R. N. COX-2: a molecular target for colorectal cancer prevention. J. Clin. Oncol. 23, 2840–2855 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Kudo, T., Narisawa, T. & Abo, S. Antitumor activity of indomethacin on methylazoxymethanol-induced large bowel tumors in rats. Gann 71, 260–264 (1980).

    CAS  PubMed  Google Scholar 

  8. Pollard, M. & Luckert, P. H. Indomethacin treatment of rats with dimethylhydrazine-induced intestinal tumors. Cancer Treat. Rep. 64, 1323–1327 (1980).

    CAS  PubMed  Google Scholar 

  9. Pollard, M. & Luckert, P. H. Treatment of chemically-induced intestinal cancers with indomethacin. Proc. Soc. Exp. Biol. Med. 167, 161–164 (1981).

    Article  CAS  PubMed  Google Scholar 

  10. Narisawa, T. et al. Inhibition of development of methylnitrosourea-induced rat colon tumors by indomethacin treatment. Cancer Res. 41, 1954–1957 (1981).

    CAS  PubMed  Google Scholar 

  11. Kune, G. A., Kune, S. & Watson, L. F. Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res. 48, 4399–4404 (1988).

    CAS  PubMed  Google Scholar 

  12. Thun, M. J., Namboodiri, M. M. & Heath, C. W. Jr . Aspirin use and reduced risk of fatal colon cancer. N. Engl. J. Med. 325, 1593–1596 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Freedman, A. N. et al. Aspirin use and p53 expression in colorectal cancer. Cancer Detect. Preven. 22, 213–218 (1998).

    Article  CAS  Google Scholar 

  14. La Vecchia, C. et al. Aspirin and colorectal cancer. Br. J. Cancer 76, 675–677 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Muscat, J. E., Stellman, S. D. & Wynder, E. L. Nonsteroidal antiinflammatory drugs and colorectal cancer. Cancer 74, 1847–1854 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Peleg, I. I., Maibach, H. T., Brown, S. H. & Wilcox, C. M. Aspirin and nonsteroidal anti-inflammatory drug use and the risk of subsequent colorectal cancer. Arch. Intern. Med. 154, 394–399 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Suh, O., Mettlin, C. & Petrelli, N. J. Aspirin use, cancer, and polyps of the large bowel. Cancer 72, 1171–1177 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Giovannucci, E. et al. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann. Intern. Med. 121, 241–246 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Giovannucci, E. et al. Aspirin and the risk of colorectal cancer in women. N. Engl. J. Med. 333, 609–614 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Schreinemachers, D. M. & Everson, R. B. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 5, 138–146 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Chan, A. T. et al. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294, 914–923 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Greenberg, E. R., Baron, J. A., Freeman, D. H. Jr, Mandel, J. S. & Haile, R. Reduced risk of large-bowel adenomas among aspirin users. The Polyp Prevention Study Group. J. Natl Cancer Inst. 85, 912–916 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Logan, R. F., Little, J., Hawtin, P. G. & Hardcastle, J. D. 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. Br. Med. J. 307, 285–289 (1993).

    Article  CAS  Google Scholar 

  24. Martinez, M. E., McPherson, R. S., Levin, B. & Annegers, J. F. Aspirin and other nonsteroidal anti-inflammatory drugs and risk of colorectal adenomatous polyps among endoscoped individuals. Cancer Epidemiol. Biomarkers. Prev. 4, 703–707 (1995).

    CAS  PubMed  Google Scholar 

  25. Harris, R. E., Beebe-Donk, J., Doss, H. & Burr Doss, D. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade. Oncol. Rep. 13, 559–583 (2005).

    CAS  PubMed  Google Scholar 

  26. Baron, J. A. et al. A randomized trial of aspirin to prevent colorectal adenomas. N. Engl. J. Med. 348, 891–899 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Sandler, R. S. et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N. Engl. J. Med. 348, 883–890 (2003). References 26 and 27 are reports of two large randomized controlled trials that illustrate that aspirin is an effective chemopreventive agent against the recurrence of colorectal adenoma after previous diagnosis of adenoma or colorectal cancer.

    Article  CAS  PubMed  Google Scholar 

  28. Corley, D. A., Kerlikowske, K., Verma, R. & Buffler, P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 124, 47–56 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Mahmud, S., Franco, E. & Aprikian, A. Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and meta-analysis. Br. J. Cancer 90, 93–99 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, W. H. et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis. J. Natl Cancer Inst. 95, 1784–1791 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Holick, C. N., Michaud, D. S., Leitzmann, M. F., Willett, W. C. & Giovannucci, E. Aspirin use and lung cancer in men. Br. J. Cancer 89, 1705–1708 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Palapattu, G. S. et al. Prostate carcinogenesis and inflammation: emerging insights. Carcinogenesis 26, 1170–1181 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Baron, J. A. Epidemiology of non-steroidal anti-inflammatory drugs and cancer. Prog. Exp. Tumor Res. 37, 1–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Harris, R. E. et al. Breast cancer and nonsteroidal anti-inflammatory drugs: prospective results from the Women's Health Initiative. Cancer Res. 63, 6096–6101 (2003).

    CAS  PubMed  Google Scholar 

  35. Terry, M. B. et al. Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291, 2433–2440 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Vane, J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol. 231, 232–235 (1971).

    Article  CAS  PubMed  Google Scholar 

  37. Taketo, M. M. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J. Natl Cancer Inst. 90, 1529–1536 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Smith, W. L., DeWitt, D. L. & Garavito, R. M. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Gupta, R. A. & Dubois, R. N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nature Rev. Cancer 1, 11–21 (2001). Excellent review of the role of COX2 in inflammation and cancer prevention.

    Article  CAS  Google Scholar 

  40. Chandrasekharan, N. V. et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl Acad. Sci. USA 99, 13926–13931 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Warner, T. D. et al. Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. J. Pharmacol. Exp. Ther. 310, 642–647 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Snipes, J. A., Kis, B., Shelness, G. S., Hewett, J. A. & Busija, D. W. Cloning and characterization of cyclooxygenase-1b (putative COX-3) in rat. J. Pharmacol. Exp. Ther. 13 Jan 2005 (10.1124/jpet.104.079533).

  43. Herschman, H. R. Prostaglandin synthase 2. Biochim. Biophys. Acta 1299, 125–140 (1996).

    Article  PubMed  Google Scholar 

  44. Mead, J., Alfin-Slater, R., Howton, D. & Popjak, G. Prostaglandins, Thromboxanes, and Prostacyclin (Plenum Press, New York, 1986).

    Book  Google Scholar 

  45. Buchanan, F. G., Wang, D., Bargiacchi, F. & DuBois, R. N. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J. Biol. Chem. 278, 35451–35457 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Pai, R. et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nature Med. 8, 289–293 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Han, C. & Wu, T. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt. J. Biol. Chem. 280, 24053–24063 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Watanabe, K. et al. Inhibitory effect of a prostaglandin E receptor subtype EP(1) selective antagonist, ONO-8713, on development of azoxymethane-induced aberrant crypt foci in mice. Cancer Lett. 156, 57–61 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Watanabe, K. et al. Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res. 59, 5093–5096 (1999).

    CAS  PubMed  Google Scholar 

  50. Mutoh, M. et al. Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res. 62, 28–32 (2002).

    CAS  PubMed  Google Scholar 

  51. Kulmacz, R. J. Cellular regulation of prostaglandin H synthase catalysis. FEBS Lett. 430, 154–157 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Chen, W., Pawelek, T. R. & Kulmacz, R. J. Hydroperoxide dependence and cooperative cyclooxygenase kinetics in prostaglandin H synthase-1 and -2. J. Biol. Chem. 274, 20301–20306 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Jaffe, B. M. Prostaglandins and cancer: an update. Prostaglandins 6, 453–461 (1974).

    Article  CAS  PubMed  Google Scholar 

  54. Bennett, A., Tacca, M. D., Stamford, I. F. & Zebro, T. Prostaglandins from tumours of human large bowel. Br. J. Cancer 35, 881–884 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rigas, B., Goldman, I. S. & Levine, L. Altered eicosanoid levels in human colon cancer. J. Lab. Clin. Med. 122, 518–523 (1993).

    CAS  PubMed  Google Scholar 

  56. Pugh, S. & Thomas, G. A. Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2. Gut 35, 675–678 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Eberhart, C. E. et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107, 1183–1188 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Kutchera, W. et al. Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc. Natl Acad. Sci. USA 93, 4816–4820 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chapple, K. S. et al. Localization of cyclooxygenase-2 in human sporadic colorectal adenomas. Am. J. Pathol. 156, 545–553 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nelson, W. G., De Marzo, A. M. & Isaacs, W. B. Prostate cancer. N. Engl. J. Med. 349, 366–381 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Backlund, M. G. et al. 15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer. J. Biol. Chem. 280, 3217–3223 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Yan, M. et al. 15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-β-induced suppressor of human gastrointestinal cancers. Proc. Natl Acad. Sci. USA 101, 17468–17473 (2004). References 61 and 62 illustrate that 15-hydroxyprostaglandin dehydrogenase, which physiologically antagonizes COX2, is abrogated in colorectal cancer as another mechanism of increased production of prostaglandins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Oshima, M. et al. Suppression of intestinal polyposis in Apc δ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Chulada, P. C. et al. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res. 60, 4705–4708 (2000). These genetic studies of ApcMin/+ mice show that COX1, in addition to COX2, has an important role in intestinal tumorigenesis.

    CAS  PubMed  Google Scholar 

  65. Hansen-Petrik, M. B. et al. Prostaglandin E(2) protects intestinal tumors from nonsteroidal anti-inflammatory drug-induced regression in ApcMin/+mice. Cancer Res. 62, 403–408 (2002).

    CAS  PubMed  Google Scholar 

  66. Capone, M. L. et al. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J. Am. Coll. Cardiol. 45, 1295–1301 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Shureiqi, I. et al. 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells. J. Natl Cancer Inst. 92, 1136–1142 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Shureiqi, I. et al. 15-Lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells. Cancer Res. 60, 6846–6850 (2000).

    CAS  PubMed  Google Scholar 

  69. Pasricha, P. J. et al. The effects of sulindac on colorectal proliferation and apoptosis in familial adenomatous polyposis. Gastroenterology 109, 994–998 (1995).

    Article  CAS  PubMed  Google Scholar 

  70. Bedi, A. et al. Inhibition of apoptosis during development of colorectal cancer. Cancer Res. 55, 1811–1816 (1995).

    CAS  PubMed  Google Scholar 

  71. Shiff, S. J., Qiao, L., Tsai, L. L. & 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. 96, 491–503 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Watson, A. J. Chemopreventive effects of NSAIDs against colorectal cancer: regulation of apoptosis and mitosis by COX-1 and COX-2. Histol. Histopathol. 13, 591–597 (1998).

    CAS  PubMed  Google Scholar 

  73. Piazza, G. A. et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res. 55, 3110–3116 (1995).

    CAS  PubMed  Google Scholar 

  74. Piazza, G. A. et al. Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res. 57, 2909–2915 (1997).

    CAS  PubMed  Google Scholar 

  75. Mahmoud, N. N. et al. The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis. Carcinogenesis 19, 87–91 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Reddy, B. S. et al. Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process. Cancer Res. 59, 3387–3391 (1999).

    CAS  PubMed  Google Scholar 

  77. Thompson, H. J. et al. Inhibition of mammary carcinogenesis in rats by sulfone metabolite of sulindac. J. Natl Cancer Inst. 87, 1259–1260 (1995).

    CAS  PubMed  Google Scholar 

  78. Shureiqi, I. et al. The 15-lipoxygenase-1 product 13–S-hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells. Proc. Natl Acad. Sci. USA 100, 9968–9973 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. He, T. C., Chan, T. A., Vogelstein, B. & Kinzler, K. W. PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99, 335–345 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Keller, H. et al. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc. Natl Acad. Sci. USA 90, 2160–2164 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yu, K. et al. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem. 270, 23975–23983 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Kliewer, S. A. et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc. Natl Acad. Sci. USA 94, 4318–4323 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992).

    Article  CAS  PubMed  Google Scholar 

  84. Nugent, K. P., Farmer, K. C., Spigelman, A. D., Williams, C. B. & Phillips, R. K. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br. J. Surg. 80, 1618–1619 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Winde, G. et al. Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal anti-inflammatory drug regimen in reversing adenomas exceeding 33 months. Dis. Colon Rectum 38, 813–830 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Reid, G. et al. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc. Natl Acad. Sci. USA 100, 9244–9249 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gray, P. A. et al. Effects of non-steroidal anti-inflammatory drugs on cyclo-oxygenase and lipoxygenase activity in whole blood from aspirin-sensitive asthmatics vs healthy donors. Br. J. Pharmacol. 137, 1031–1038 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Davies, N. M. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis. Colon Rectum 38, 1311–1321 (1995).

    Article  CAS  PubMed  Google Scholar 

  89. Murray, M. D. & Brater, D. C. Renal toxicity of the nonsteroidal anti-inflammatory drugs. Annu. Rev. Pharmacol. Toxicol. 33, 435–465 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Silverstein, F. E. et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284, 1247–1255 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Laine, L., Wogen, J. & Yu, H. Gastrointestinal health care resource utilization with chronic use of COX-2-specific inhibitors versus traditional NSAIDs. Gastroenterology 125, 389–395 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Bresalier, R. S. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092–1102 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Nussmeier, N. A. et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N. Engl. J. Med. 352, 1081–1091 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Solomon, S. D. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071–1080 (2005). References 92–94 show results from several large randomized controlled trials that provide unequivocal evidence of the cardiotoxicity of COXibs.

    Article  CAS  PubMed  Google Scholar 

  95. Fitzgerald, G. A. Coxibs and cardiovascular disease. N. Engl. J. Med. 351, 1709–1711 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Marcus, A. J., Broekman, M. J. & Pinsky, D. J. COX inhibitors and thromboregulation. N. Engl. J. Med. 347, 1025–1026 (2002).

    Article  PubMed  Google Scholar 

  97. Muscara, M. N. et al. Selective cyclo-oxygenase-2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence. Br. J. Pharmacol. 129, 1423–1430 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bombardier, C. et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343, 1520–1528 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. DuBois, R. N. New paradigms for cancer prevention. Carcinogenesis 22, 691–692 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Alberts, D. S. et al. What happened to the coxibs on the way to the cardiologist? Cancer Epidemiol. Biomarkers Prev. 14, 555–556 (2005).

    Article  PubMed  Google Scholar 

  101. Advisory panel weighs COX-2 inhibitors' fate. NCI Cancer Bull. 2, 1–2 (2005).

  102. Undevia, S. D., Gomez-Abuin, G. & Ratain, M. J. Pharmacokinetic variability of anticancer agents. Nature Rev. Cancer 5, 447–458 (2005).

    Article  CAS  Google Scholar 

  103. Ulrich, C. M., Robien, K. & McLeod, H. L. Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nature Rev. Cancer 3, 912–920 (2003).

    Article  CAS  Google Scholar 

  104. Asano, T. K. & McLeod, R. S. Nonsteroidal anti-inflammatory drugs and aspirin for the prevention of colorectal adenomas and cancer: a systematic review. Dis. Colon Rectum 47, 665–673 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Herendeen, J. M. & Lindley, C. Use of NSAIDs for the chemoprevention of colorectal cancer. Ann. Pharmacother. 37, 1664–1674 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Koehne, C. H. & Dubois, R. N. COX-2 inhibition and colorectal cancer. Semin. Oncol. 31, 12–21 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Steinbach, G. et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342, 1946–1952 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Limburg, P. J. et al. Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib. Gastroenterology 129, 863–873 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Needs, C. J. & Brooks0, P. M. Clinical pharmacokinetics of the salicylates. Clin. Pharmacokinet. 10, 164–177 (1985).

    Article  CAS  PubMed  Google Scholar 

  110. Janssen, F. W. et al. Metabolism and kinetics of oxaprozin in normal subjects. Clin. Pharmacol. Ther. 27, 352–362 (1980).

    Article  CAS  PubMed  Google Scholar 

  111. Karim, A. et al. Oxaprozin and piroxicam, nonsteroidal antiinflammatory drugs with long half-lives: effect of protein-binding differences on steady-state pharmacokinetics. J. Clin. Pharmacol. 37, 267–278 (1997).

    Article  CAS  PubMed  Google Scholar 

  112. Cryer, B. & Feldman, M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am. J. Med. 104, 413–421 (1998).

    Article  CAS  PubMed  Google Scholar 

  113. Fries, S. et al. Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology 130, 55–64 (2006). Pharmacokinetic study indicating that genetic polymorphisms in COX1 and possibly CYP2C9 can alter the kinetics of COX inihibitors.

    Article  CAS  PubMed  Google Scholar 

  114. O'Neil, W. M., Pezzullo, J. C., Di Girolamo, A., Tsoukas, C. M. & Wainer, I. W. Glucuronidation and sulphation of paracetamol in HIV-positive patients and patients with AIDS. Br. J. Clin. Pharmacol. 48, 811–818 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hutt, A. J., Caldwell, J. & Smith, R. L. The metabolism of aspirin in man: a population study. Xenobiotica 16, 239–249 (1986).

    Article  CAS  PubMed  Google Scholar 

  116. Tracy, T. S., Marra, C., Wrighton, S. A., Gonzalez, F. J. & Korzekwa, K. R. Studies of flurbiprofen 4′-hydroxylation. Additional evidence suggesting the sole involvement of cytochrome P450 2C9. Biochem. Pharmacol. 52, 1305–1309 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Hamman, M. A., Thompson, G. A. & Hall, S. D. Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem. Pharmacol. 54, 33–41 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Bort, R., Ponsoda, X., Carrasco, E., Gomez-Lechon, M. J. & Castell, J. V. Metabolism of aceclofenac in humans. Drug Metab. Dispos. 24, 834–841 (1996).

    CAS  PubMed  Google Scholar 

  119. Chesne, C. et al. Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4. Xenobiotica 28, 1–13 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Nakajima, M. et al. Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. Drug Metab. Dispos. 26, 261–266 (1998).

    CAS  PubMed  Google Scholar 

  121. Zhao, J., Leemann, T. & Dayer, P. In vitro oxidation of oxicam NSAIDS by a human liver cytochrome P450. Life Sci. 51, 575–581 (1992).

    Article  CAS  PubMed  Google Scholar 

  122. Miners, J. O., Coulter, S., Tukey, R. H., Veronese, M. E. & Birkett, D. J. Cytochromes P450, 1A2, and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen. Biochem. Pharmacol. 51, 1003–1008 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Furuta, S. et al. Involvement of CYP2C9 and UGT2B7 in the metabolism of zaltoprofen, a nonsteroidal anti-inflammatory drug, and its lack of clinically significant CYP inhibition potential. Br. J. Clin. Pharmacol. 54, 295–303 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cheng, Z., Radominska-Pandya, A. & Tephly, T. R. Studies on the substrate specificity of human intestinal UDP-lucuronosyltransferases 1A8 and 1A10. Drug Metab. Dispos. 27, 1165–1170 (1999).

    CAS  PubMed  Google Scholar 

  125. Jin, C., Miners, J. O., Lillywhite, K. J. & Mackenzie, P. I. Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs. J. Pharmacol. Exp. Ther. 264, 475–479 (1993).

    CAS  PubMed  Google Scholar 

  126. Sabolovic, N., Magdalou, J., Netter, P. & Abid, A. Nonsteroidal anti-inflammatory drugs and phenols glucuronidation in Caco-2 cells: identification of the UDP-glucuronosyltransferases UGT1A6, 1A3 and 2B7. Life Sci. 67, 185–196 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Zhang, J. Y., Zhan, J., Cook, C. S., Ings, R. M. & Breau, A. P. Involvement of human UGT2B7 and 2B15 in rofecoxib metabolism. Drug Metab. Dispos. 31, 652–658 (2003).

    Article  PubMed  Google Scholar 

  128. Kuehl, G. E., Lampe, J. W., Potter, J. D. & Bigler, J. Glucuronidation of nonsteroidal anti-inflammatory drugs (NSAIDs): identifying the enzymes responsible in human liver microsomes. Drug Metab. Dispos. 33, 1027–1035 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Lee, C. R., Goldstein, J. A. & Pieper, J. A. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12, 251–263 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Burchell, B. Genetic variation of human UDP-glucuronosyltransferase: implications in disease and drug glucuronidation. Am. J. Pharmacogenomics 3, 37–52 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Ciotti, M., Marrone, A., Potter, C. & Owens, I. S. Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications. Pharmacogenetics 7, 485–495 (1997).

    Article  CAS  PubMed  Google Scholar 

  132. Miners, J. O., Grgurinovich, N., Whitehead, A. G., Robson, R. A. & Birkett, D. J. Influence of gender and oral contraceptive steroids on the metabolism of salicylic acid and acetylsalicylic acid. Br. J. Clin. Pharmacol. 22, 135–142 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Macdonald, J. I., Herman, R. J. & Verbeeck, R. K. Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal. Eur. J. Clin. Pharmacol. 38, 175–179 (1990).

    CAS  PubMed  Google Scholar 

  134. Emery, P., Kong, S. X., Ehrich, E. W., Watson, D. J. & Towheed, T. E. Dose–effect relationships of nonsteroidal anti-inflammatory drugs: a literature review. Clin. Ther. 24, 1225–1291 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Tang, C. et al. In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 11, 223–235 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Takanashi, K. et al. CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 10, 95–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. Kirchheiner, J. et al. Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics 13, 473–480 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Bigler, J. et al. CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk. Cancer Res. 61, 3566–3569 (2001). First report to show that polymorphisms in CYP2C9 and UGT1A6 modify the risk reduction of colorectal adenoma associated with NSAID use.

    CAS  PubMed  Google Scholar 

  139. Chan, A. T., Tranah, G. J., Giovannucci, E. L., Hunter, D. J. & Fuchs, C. S. Genetic variants in the UGT1A6 enzyme, aspirin use, and the risk of colorectal adenoma. J. Natl Cancer Inst. 97, 457–460 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Variation Discovery Resource. http://pga.gs.washington.edu/ (2006).

  141. Ulrich, C. M. et al. Cyclooxygenase 1 (COX1) polymorphisms in African-American and Caucasian populations. Hum. Mutat. 20, 409–410 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Halushka, M. K. et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nature Genet. 22, 239–247 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Halushka, M. K., Walker, L. P. & Halushka, P. V. Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin. Pharmacol. Ther. 73, 122–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Fritsche, E. et al. Functional characterization of cyclooxygenase-2 polymorphisms. J. Pharmacol. Exp. Ther. 299, 468–476 (2001).

    CAS  PubMed  Google Scholar 

  145. Ulrich, C. M. et al. Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure. Hum. Mutat. 26, 394–395 (2005).

    Article  PubMed  Google Scholar 

  146. Cipollone, F. et al. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA 291, 2221–2228 (2004).

    Article  CAS  PubMed  Google Scholar 

  147. Campa, D. et al. Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25, 229–235 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Koh, W. P., Yuan, J. M., Van Den Berg, D., Lee, H. P. & Yu, M. C. Interaction between cyclooxygenase-2 gene polymorphism and dietary n-6 polyunsaturated fatty acids on colon cancer risk: the Singapore Chinese Health Study. Br. J. Cancer 90, 1760–1764 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Cox, D. G. et al. Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer. Br. J. Cancer 91, 339–343 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ulrich, C. M. et al. PTGS2 (COX-2)-765G > C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs. Cancer Epidemiol. Biomarkers Prev. 14, 616–619 (2005). First study showing that a promoter polymorphism in COX2 might reduce the risk of colorectal adenoma and modulate the protective effect of NSAID use on adenoma risk.

    Article  CAS  PubMed  Google Scholar 

  151. Lin, H. J. et al. Prostaglandin H synthase 2 variant (Val511Ala) in African Americans may reduce the risk for colorectal neoplasia. Cancer Epidemiol. Biomarkers Prev. 11, 1305–1315 (2002).

    CAS  PubMed  Google Scholar 

  152. Papafili, A. et al. Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler. Thromb. Vasc. Biol. 22, 1631–1636 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. Ulrich, C. M. et al. Polymorphisms in PTGS1 (=COX-1) and risk of colorectal polyps. Cancer Epidemiol. Biomarkers Prev. 13, 889–893 (2004). Epidemiological study of COX1 polymorphisms suggesting that inherited polymorphisms in COX1 modify the protective effects of NSAID use on colorectal adenoma risk.

    CAS  PubMed  Google Scholar 

  154. Poole, E. et al. Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps. Cancer Epidemiol. Biomarkers Prev. (in the press).

  155. Thomas, D. C. The need for a systematic approach to complex pathways in molecular epidemiology. Cancer Epidemiol. Biomarkers Prev. 14, 557–559 (2005).

    Article  PubMed  Google Scholar 

  156. Egan, K. M. et al. COX-2-derived prostacyclin confers atheroprotection on female mice. Science 306, 1954–1957 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Nakayama, T., Soma, M. & Kanmatsuse, K. Organization of the human prostacyclin synthase gene and association analysis of a novel CA repeat in essential hypertension. Adv. Exp. Med. Biol. 433, 127–130 (1997).

    Article  CAS  PubMed  Google Scholar 

  158. Chevalier, D. et al. Characterization of new mutations in the coding sequence and 5′-untranslated region of the human prostacyclin synthase gene (CYP8A1). Hum. Genet. 108, 148–155 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Nakayama, T. et al. Association of 5′ upstream promoter region of prostacyclin synthase gene variant with cerebral infarction. Am. J. Hypertens. 13, 1263–1267 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Nakayama, T. et al. Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction. Am. Heart J. 143, 797–801 (2002).

    Article  CAS  PubMed  Google Scholar 

  161. Chevalier, D. et al. Sequence analysis, frequency and ethnic distribution of VNTR polymorphism in the 5′-untranslated region of the human prostacyclin synthase gene (CYP8A1). Prostaglandins Other Lipid Mediat. 70, 31–37 (2002).

    Article  CAS  PubMed  Google Scholar 

  162. Nakayama, T. et al. Novel polymorphic CA/TG repeat identified in the human prostacyclin synthase gene. Hum. Hered. 47, 176–177 (1997).

    Article  CAS  PubMed  Google Scholar 

  163. Omenn, G. S. et al. Risk factors for lung cancer and for intervention effects in CARET, the β-Carotene and Retinol Efficacy Trial. J. Natl Cancer Inst. 88, 1550–1559 (1996).

    Article  CAS  PubMed  Google Scholar 

  164. Touvier, M., Kesse, E., Clavel-Chapelon, F. & Boutron-Ruault, M. C. Dual Association of β-carotene with risk of tobacco-related cancers in a cohort of French women. J. Natl Cancer Inst. 97, 1338–1344 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Richard Kulmacz for comments on the review and Elizabeth Poole and Linda Massey for assistance with the manuscript.

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Correspondence to Cornelia M. Ulrich.

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DATABASES

National Cancer Institute

colorectal cancer

gastric cancer

oesophageal adenocarcinoma

FURTHER INFORMATION

ClinicalTrials.Gov web site

Cornelia M. Ulrich's web page

dbSNP web site

John D. Potter's web page

University of Washington–Fred Hutchinson Cancer Research Center Variation Discovery Resource

Glossary

Antipyretics

Antipyretics are drugs that prevent or reduce fever by lowering the body temperature from a raised state.

Analgesics

Any member of the diverse group of drugs that are used to relieve pain. Analgesics include NSAIDs, narcotic drugs such as morphine, and synthetic drugs with narcotic properties.

Free radicals

Free radicals are atoms with an unpaired electron. Many are highly reactive and can easily damage biological molecules.

Eicosanoids

Multipotent signalling molecules that function in both an autocrine and paracrine fashion. They include the leukotrienes and prostaglandins.

Odds ratio and relative risk

The odds ratio in case–control studies is an approximation of the relative risk, which defines the risk of disease of a group of individuals who are exposed to a certain factor (for example, NSAIDs) relative to those who are not exposed.

Metachronous

Occurring at another time. When an individual develops a second polyp, this is not recurrent in the way that we describe the re-emergence of a primary cancer because the second polyp is almost always a separate pathological event, separated in space (location in the colon) and time from the first.

Polymorphism

A location in the human genome where at least two sequence variants exist in the human population with appreciable frequency (>1%). Polymorphisms can include single-nucleotide polymorphisms, deletions and insertions, or a variable number of a specific repeated sequence.

dbSNP rs20417

This nomenclature denotes the registered number of a polymorphism in the dbSNP database.

C-reactive protein

An acute-phase protein and non-specific marker of inflammation that is secreted by the liver in response to pro-inflammatory cytokines, such as interleukin 6. Interleukin 6 synthesis can be regulated by cyclooxygenase 2 through the production of prostaglandin E2.

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Ulrich, C., Bigler, J. & Potter, J. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 6, 130–140 (2006). https://doi.org/10.1038/nrc1801

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