, Volume 67, Issue 6, pp 821–845

Cyclo-Oxygenase-2 and its Inhibition in Cancer

Is There a Role?
Current Opinion


Despite recent improvements in chemotherapy and radiation therapy in cancer management with the addition of biological agents, novel treatment approaches are needed to further benefit patients. Cyclo-oxygenase (COX)-2 inhibition represents one such possibility. COX-2 is an enzyme induced in pathological states such as inflammatory disorders and cancer, where it mediates production of prostanoids. The enzyme is commonly expressed in both premalignant lesions and malignant tumours of different types. A growing body of evidence suggests an association of COX-2 with tumour development, aggressive biological tumour behaviour, resistance to standard cancer treatment, and adverse patient outcome. COX-2 may be related to cancer development and propagation through multiple mechanisms, including stimulation of growth, migration, invasiveness, resistance to apoptosis, suppression of the immunosurveillance system, and enhancement of angiogenesis. Epidemiological data suggest that NSAIDs and selective COX-2 inhibitors might prevent the development of cancers, including colorectal, oesophageal and lung cancer. Preclinical investigations have demonstrated that inhibition of this enzyme with selective COX-2 inhibitors enhances tumour response to radiation and chemotherapeutic agents. These preclinical findings have been rapidly advanced to clinical oncology. Clinical trials of the combination of selective COX-2 inhibitors with radiotherapy, chemotherapy or both in patients with a number of cancers have been initiated, and preliminary results are encouraging. This review discusses the role of COX-2, its products (prostaglandins) and its inhibitors in tumour growth and treatment.


  1. 1.
    Fu JY, Masferrer JL, Seibert K, et al. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 1990; 265: 16737–40PubMedGoogle Scholar
  2. 2.
    O’Banion MK. Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology. Crit Rev Neurobiol 1999; 13: 45–82PubMedGoogle Scholar
  3. 3.
    Williams CS, DuBois RN. Prostaglandin endoperoxide synthase: why two isoforms? Am J Physiol 1996; 270: G393–400PubMedGoogle Scholar
  4. 4.
    Milas L, Mason K, Liao Z, et al. Role of Cyclooxygenase-2 (COX-2) and its inhibition in tumor biology and radiotherapy. In: Nieder C, Milas L, Ang K, editors. Modification of radiation response. New York: Springer-Verlag, 2003: 241–58CrossRefGoogle Scholar
  5. 5.
    Bakhle Y. COX-2 and cancer: a new approach to an old problem. Br J Pharmacol 2001; 134: 1137–50PubMedCrossRefGoogle Scholar
  6. 6.
    Dannenberg AJ, Lippman SM, Mann JR, et al. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005; 23: 254–66PubMedCrossRefGoogle Scholar
  7. 7.
    Dannhardt G, Kiefer W. Cyclooxygenase inhibitors: current status and future prospects. Eur J Med Chem 2001; 36: 109–26PubMedCrossRefGoogle Scholar
  8. 8.
    Komaki R, Liao Z, Milas L. Improvement strategies for molecular targeting: cyclooxygenase-2 inhibitors as radiosensitizers for non-small cell lung cancer. Semin Oncol 2004; 31 (41 Suppl. 41): 47–51PubMedCrossRefGoogle Scholar
  9. 9.
    Liao Z, Milas L. COX-2 and its inhibition as a molecular target in the prevention and treatment of lung cancer. Expert Rev Anticancer Therapy 2004; 4: 543–60CrossRefGoogle Scholar
  10. 10.
    Marnett J. Cyclooxyenase mechanisms. Curr Opin Chem Biol 2000; 4: 545–52PubMedCrossRefGoogle Scholar
  11. 11.
    Subbaramaiah K, Dannenberg A. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trend Pharmacol Sci 2003; 24: 96–102CrossRefGoogle Scholar
  12. 12.
    Wang D, DuBois RN. Prostaglandins and cancer. Gut 2006; 55: 115–22PubMedCrossRefGoogle Scholar
  13. 13.
    Wang D, Mann J, DuBois R. The role of prostaglandins and other eicosanoids in the gastrointestinal tract. Gastroenterology 2005; 128: 1445–65PubMedCrossRefGoogle Scholar
  14. 14.
    Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem 1987; 56: 615–49PubMedCrossRefGoogle Scholar
  15. 15.
    Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J 1989; 259: 315–24PubMedGoogle Scholar
  16. 16.
    Forman B, Chen J, Evans R. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. PNAS 1997; 94: 4312–7PubMedCrossRefGoogle Scholar
  17. 17.
    Forman B, Tontonoz P, Chen J, et al. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995; 83: 803–12PubMedCrossRefGoogle Scholar
  18. 18.
    Lemberger T, Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: a nuclear receptor signalling pathway in lipid physiology. Annu Rev Cell Dev Biol 1996; 12: 335–63PubMedCrossRefGoogle Scholar
  19. 19.
    Lim H, Gupta RA, Ma W, et al. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes Dev 1999; 13: 1561–74PubMedCrossRefGoogle Scholar
  20. 20.
    Bansal P, Sonnenberg A. Risk factors of colorectal cancer in inflammatory bowel disease. Am J Gastroenterol 1996; 91: 44–8PubMedGoogle Scholar
  21. 21.
    Giovannucci E, Rimm E, Stampfer M, et al. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Inter Med 1994; 121: 241–6Google Scholar
  22. 22.
    Thun M, Namboodiri M, Calle E, et al. Aspirin use and risk of fatal cancer. Cancer Res 1993; 53: 1322–7PubMedGoogle Scholar
  23. 23.
    Schreinemachers DM, Everson RB. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994; 5: 138–46PubMedCrossRefGoogle Scholar
  24. 24.
    Eberhart C, Coffey R, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107: 1183–8PubMedGoogle Scholar
  25. 25.
    Koki A, Leahy KM, Masferrer JL. Potential utility of COX-2 inhibitors in chemoprevention and chemotherapy. Expet Opin Investig Drugs 1999; 8: 1623–38CrossRefGoogle Scholar
  26. 26.
    Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 87: 803–9PubMedCrossRefGoogle Scholar
  27. 27.
    Liu CH, Chang S-H, Narko K, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001; 276: 18563–9PubMedCrossRefGoogle Scholar
  28. 28.
    Chang S-H, Ai Y, Breyer RM, et al. The prostaglandin E2 receptor EP2 Is required for cyclooxygenase 2-mediated mammary hyperplasia. Cancer Res 2005; 65: 4496–9PubMedCrossRefGoogle Scholar
  29. 29.
    Krysan K, Reckamp KL, Dalwadi H, et al. Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signalling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Res 2005; 65: 6275–81PubMedCrossRefGoogle Scholar
  30. 30.
    Han S, Roman J. COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sites. Int J Cancer 2005; 116: 536–46PubMedCrossRefGoogle Scholar
  31. 31.
    Alshafie G, Abou-Issa H, Seibert K, et al. Chemotherapeutic evaluation of celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model. Oncol Report 2000; 7: 1377–8Google Scholar
  32. 32.
    Dannenberg A, Subbaramaiah K. Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 2003; 4: 431–6PubMedCrossRefGoogle Scholar
  33. 33.
    Fischer SM, Lo HH, Gordon GB, et al. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol Carcinog 1999; 25: 231–40PubMedCrossRefGoogle Scholar
  34. 34.
    Harris RE, Alshafie GA, Abou-Issa H, et al. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 2000; 60: 2101–3PubMedGoogle Scholar
  35. 35.
    Jacoby RF, Seibert K, Cole CE, et al. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 2000; 60: 5040–4PubMedGoogle Scholar
  36. 36.
    Oshima M, Murai N, Kargman S, et al. Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res 2001; 61: 1733–40PubMedGoogle Scholar
  37. 37.
    Zamuner SR, Bak AW, Devchand PR, et al. Predisposition to colorectal cancer in rats with resolved colitis: role of cyclooxygenase-2-derived prostaglandin D 2. Am J Pathol 2005; 167: 1293–300PubMedCrossRefGoogle Scholar
  38. 38.
    Reddy BS, Patlolla JM, Simi B, et al. Prevention of colon cancer by low doses of celecoxib, a cyclooxygenase inhibitor, administered in diet rich in (omega)-3 polyunsaturated fatty acids. Cancer Res 2005; 65: 8022–7PubMedCrossRefGoogle Scholar
  39. 39.
    Albazaz R, Verbeke C, Rahman S, et al. Cyclooxygenase-2 expression associated with severity of pain lesions: a possible link between chronic pancreatitis and pancreatic cancer. Pancreatology 2005; 4: 361–9CrossRefGoogle Scholar
  40. 40.
    Zhang X, Miao X, Tan W, et al. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology 2005; 129: 565–76PubMedGoogle Scholar
  41. 41.
    Kang S, Kim Y, Kim M, et al. Polymorphism in the nuclear factor kappa-B binding promoter region of cyclooxygenase-2 is associated with an increased risk of bladder cancer. Cancer Lett 2005; 217: 11–6PubMedCrossRefGoogle Scholar
  42. 42.
    Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946–52PubMedCrossRefGoogle Scholar
  43. 43.
    Mao JT, Fishbein MC, Adams B, et al. Celecoxib decreases Ki-67 proliferative index in active smokers. Clin Cancer Res 2006; 12: 314–20PubMedCrossRefGoogle Scholar
  44. 44.
    Furuta Y, Hall ER, Sanduja S, et al. Prostaglandin production by murine tumors as a predictor for therapeutic response to indomethacin. Cancer Res 1988; 48: 3002–7PubMedGoogle Scholar
  45. 45.
    Tang D, Honn KV. Eicosanoids and tumor cell metastasis. In: Steiner M, Richardson PD, editors. Prostaglandin inhibitors in tumor immunology and immunotherapy. Boca Raton (FL): CRC Press, 1994: 73–108Google Scholar
  46. 46.
    Bennett A, Berstock DA, Raja B, et al. Survival time after surgery is inversely related to the amounts of prostaglandins extracted from human breast cancers [proceedings]. Br J Pharmacol 1979; 66: 451Google Scholar
  47. 47.
    Rigas B, Goldman IS, Levine L. Altered eicosanoid levels in human colon cancer. J Lab Clin Med 1993; 122: 518–23PubMedGoogle Scholar
  48. 48.
    Chan G, Boyle JO, Yang EK, et al. Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res 1999; 59: 991–4PubMedGoogle Scholar
  49. 49.
    Buskens C, Van Rees B, Sivula A, et al. Prognostic significance of elevated cyclooxygenase 2 expression in patients with adenocarcinoma of the esophagus. Gastroenterology 2002; 122: 1800–7PubMedCrossRefGoogle Scholar
  50. 50.
    Wilson K, Fu S, Ramanujam K, et al. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett’s esophagus and associated adenocarcinomas. Cancer Res 1998; 58: 2929–34PubMedGoogle Scholar
  51. 51.
    Uefuji K, Ichikura T, Mochizuki H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas. J Surg Oncol 2001; 76: 26–30PubMedCrossRefGoogle Scholar
  52. 52.
    Jang TJ. Expression of proteins related to prostaglandin E2 biosynthesis is increased in human gastric cancer and during gastric carcinogenesis. Virchows Arch 2004; 445: 564–71PubMedCrossRefGoogle Scholar
  53. 53.
    Sheehan KM, Sheahan K, O’Donoghue DP, et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 1999; 282: 1254–7PubMedCrossRefGoogle Scholar
  54. 54.
    Sano H, Kawahito Y, Wilder RL, et al. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 1995; 55: 3785–9PubMedGoogle Scholar
  55. 55.
    Hao X, Bishop A, Wallace MB, et al. Early expression of cyclooxygenase-2 during sporadic colorectal carcinogenesis. J Pathol 1999; 187: 295–301PubMedCrossRefGoogle Scholar
  56. 56.
    Soumaoro LT, Uetake H, Higuchi T, et al. Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res 2004; 10: 8465–71PubMedCrossRefGoogle Scholar
  57. 57.
    Shiota G, Okubo M, Noumi T, et al. Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterology 1999; 46: 407–12PubMedGoogle Scholar
  58. 58.
    Niijima M, Yamaguchi T, Ishihara T, et al. Immunohistochemical analysis and in situ hybridization of cyclooxygenase-2 expression in intraductal papillary-mucinous tumors of the pancreas. Cancer 2002; 94: 1565–73PubMedCrossRefGoogle Scholar
  59. 59.
    Tucker ON, Dannenberg AJ, Yang EK, et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999; 59: 987–90PubMedGoogle Scholar
  60. 60.
    Ristimaki A, Sivula A, Lundin J, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 2002; 62: 632–5PubMedGoogle Scholar
  61. 61.
    Achiwa H, Yatabe Y, Hida T, et al. Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin Cancer Res 1999; 5: 1001–5PubMedGoogle Scholar
  62. 62.
    Wolff H, Saukkonen K, Anttila S, et al. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998; 58: 4997–5001PubMedGoogle Scholar
  63. 63.
    Xing L, Zhang Z, Xu Y, et al. Expression and significance of cyclooxygenase 2 gene in lung cancer. J Huazhong Univ Sci Technolog Med Sci 2004; 24: 326–8PubMedCrossRefGoogle Scholar
  64. 64.
    Ristimaki A, Nieminen O, Saukkonen K, et al. Expression of cyclooxygenase-2 in human transitional cell carcinoma of the urinary bladder. Am J Pathol 2001; 158: 849–53PubMedCrossRefGoogle Scholar
  65. 65.
    Sales KJ, Katz AA, Davis M, et al. Cyclooxygenase-2 expression and prostaglandin E2 synthesis are up-regulated in carcinomas of the cervix: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors. J Clin Endocrinol Metab 2001; 86: 2243–9PubMedCrossRefGoogle Scholar
  66. 66.
    Kulkarni S, Rader JS, Zhang F, et al. Cyclooxygenase-2 is overexpressed in human cervical cancer. Clin Cancer Res 2001; 7: 429–34PubMedGoogle Scholar
  67. 67.
    Denkert C, Kobel M, Pest S, et al. Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma. Am J Pathol 2002; 160: 893–903PubMedCrossRefGoogle Scholar
  68. 68.
    Lee L, Pan C, Cheng C, et al. Expression of cyclooxygenase-2 in prostate adenocarcinoma and benign prostatic hyperplasia. Anticancer Res 2001; 21: 1291–4PubMedGoogle Scholar
  69. 69.
    Denkert C, Kobel M, Berger S, et al. Expression of cyclooxygenase 2 in human malignant melanoma. Cancer Res 2001; 61: 303–8PubMedGoogle Scholar
  70. 70.
    Soslow R, Dannenberg A, Rush D, et al. COX-2 is expressed in human pulmonary, colonie, and mammary tumors. Cancer 2000; 89: 2637–45PubMedCrossRefGoogle Scholar
  71. 71.
    Cianchi F, Cortesini C, Bechi P, et al. Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology 2001; 121: 1339–47PubMedCrossRefGoogle Scholar
  72. 72.
    Saukkonen K, Nieminen O, van Rees B, et al. Expression of cyclooxygenase-2 in dysplasia of the stomach and in intestinal-type gastric adenocarcinoma. Clin Cancer Res 2001; 7: 1923–31PubMedGoogle Scholar
  73. 73.
    Sung JJY, Leung WK, Go MYY, et al. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol 2000; 157: 729–35PubMedCrossRefGoogle Scholar
  74. 74.
    Zimmerman K, Sarbia M, Weber A, et al. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 1999; 59: 198–204Google Scholar
  75. 75.
    Merati K, Siadaty M, Andea A, et al. Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters. Am J Clin Oncol 2001; 24: 447–52PubMedCrossRefGoogle Scholar
  76. 76.
    Koshiba T, Hosotani R, Miyamoto Y, et al. Immunohistochemical analysis of cyclooxygenase-2 expression in pancreatic tumors. Int J Pancreatol 1999; 26: 69–76PubMedCrossRefGoogle Scholar
  77. 77.
    Kokawa A, Kondo H, Gotoda T, et al. Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors. Cancer 2001; 91: 333–9PubMedCrossRefGoogle Scholar
  78. 78.
    Bae SH, Jung ES, Park YM, et al. Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res 2001; 7: 1410–8PubMedGoogle Scholar
  79. 79.
    Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998; 58: 3761–4PubMedGoogle Scholar
  80. 80.
    Hasturk S, Kemp B, Kalapurakal S, et al. Expression of cyclooxygenase-1 and cyclooxygenase-2 in bronchial epithelium and nonsmall cell lung carcinoma. Cancer 2002; 94: 1023–9PubMedCrossRefGoogle Scholar
  81. 81.
    Zha S, Gage WR, Sauvageot J, et al. Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. Cancer Res 2001; 61: 8617–23PubMedGoogle Scholar
  82. 82.
    Shirahama T. Cyclooxygenase-2 expression is up-regulated in transitional cell carcinoma and Its preneoplastic lesions in the human urinary bladder. Clin Cancer Res 2000; 6: 2424–30PubMedGoogle Scholar
  83. 83.
    Komhoff M, Guan Y, Shappell HW, et al. Enhanced expression of cyclooxygenase-2 in high grade human transitional cell bladder carcinomas. Am J Pathol 2000; 157: 29–35PubMedCrossRefGoogle Scholar
  84. 84.
    Half E, Tang XM, Gwyn K, et al. Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res 2002; 62: 1676–81PubMedGoogle Scholar
  85. 85.
    Ryu H-S, Chang K-H, Yang H-W, et al. High cyclooxygenase-2 expression in stage IB cervical cancer with lymph node metastasis or parametrial invasion. Gynecol Oncol 2000; 76: 320–5PubMedCrossRefGoogle Scholar
  86. 86.
    Gaffney DK, Holden J, Davis M, et al. Elevated cyclooxygenase-2 expression correlates with diminished survival in carcinoma of the cervix treated with radiotherapy. Int J Radiat Oncol Biol Phys 2001; 49: 1213–7PubMedCrossRefGoogle Scholar
  87. 87.
    Ferrandina G, Legge F, Ranelletti F, et al. Cyclooxygenase-2 expression in endometrial carcinoma: correlation with clinicopathologic parameters and clinical outcome. Cancer 2002; 95: 801–7PubMedCrossRefGoogle Scholar
  88. 88.
    Matsumoto Y, Ishiko O, Deguchi M, et al. Cyclooxygenase-2 expression in normal ovaries and epithelial ovarian neoplasms. Int J Mol Med 2001; 8: 31–6PubMedGoogle Scholar
  89. 89.
    Thompson E, Gupta A, Vielhauer G, et al. The growth of malignant keratinocytes depends on signalling through the PGE (2) receptor EP 1. Neoplasia 2001; 3: 402–10PubMedCrossRefGoogle Scholar
  90. 90.
    Subbaramaiah K, Norton L, Gerald W, et al. Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA 3. J Biol Chem 2002; 277: 18649–57PubMedCrossRefGoogle Scholar
  91. 91.
    Hida T, Leyton J, Makheja A, et al. Non-small cell lung cancer cyclooxygenase activity and proliferation are inhibited by non-steroidal antiinflammatory drugs. Anticancer Res 1998; 18: 775–82PubMedGoogle Scholar
  92. 92.
    Khuri FR, Wu H, Lee JJ, et al. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001; 7: 861–7PubMedGoogle Scholar
  93. 93.
    Yamauchi T, Watanabe M, Hasegawa H, et al. The role of COX-2 expression in colorectal cancer. Proc Am Assoc Cancer Res 2000; 41: 342Google Scholar
  94. 94.
    Murata H, Kawano S, Tsuji S, et al. Cyclooxygenase-2 overexpression enhances lymphatic invasion and metastasis in human gastric carcinoma. Am J Gastroenterol 1999; 94: 451–5PubMedCrossRefGoogle Scholar
  95. 95.
    Kargman SL, O’Neill GP, Vickers PJ, et al. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res 1995; 55: 2556–9PubMedGoogle Scholar
  96. 96.
    Fux R, Schwab M, Thon K-P, et al. Cyclooxygenase-2 expression in human colorectal cancer is unrelated to overall patient survival. Clin Cancer Res 2005; 11: 4754–60PubMedCrossRefGoogle Scholar
  97. 97.
    Mrena J, Wiksten J-P, Thiel A, et al. Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res 2005; 11: 7362–8PubMedCrossRefGoogle Scholar
  98. 98.
    Xi H, Baldus SE, Warnecke-Eberz U, et al. High cyclooxygenase-2 expression following neoadjuvant radiochemotherapy is associated with minor histopathologic response and poor prognosis in esophageal cancer. Clin Cancer Res 2005; 11: 8341–7PubMedCrossRefGoogle Scholar
  99. 99.
    Heeren P, Plukker J, van Dullemen H, et al. Prognostic role of cyclooxygenase-2 expression in esophageal carcinoma. Cancer Lett 2005; 225: 283–9PubMedCrossRefGoogle Scholar
  100. 100.
    von Rahden BHA, Stein HJ, Puhringer F, et al. Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma. Cancer Res 2005; 65: 5038–44CrossRefGoogle Scholar
  101. 101.
    Laga A, Zander DS, Cagle P. Prognostic significance of cyclooxygenase 2 expression in 259 cases of non-small cell lung cancer. Arch Pathol Lab Med 2005; 129: 1113–7PubMedGoogle Scholar
  102. 102.
    Fowler J, Ramirez N, Cohn D, et al. Correlation of cyclooxygenase-2 (COX-2) and aromatase expression in human endometrial cancer: tissue microarray analysis. Am J Obstet Gynecol 2005; 19: 1262–71CrossRefGoogle Scholar
  103. 103.
    Pyo H, Kim Y, Cho N, et al. Coexpression of cyclooxygenase-2 and thymidine phosphorylase as a prognostic indicator in patients with FIGO stage IIB squamous cell carcinoma of uterine cervix treated with radiotherapy and concurrent chemotherapy. Int J Radiat Oncol Biol Phys 2005; 62: 725–32PubMedCrossRefGoogle Scholar
  104. 104.
    Kozaki K, Koshikawa K, Tatematsu Y, et al. Multi-faceted analyses of a highly metastatic human lung cancer cell line NCI-H460-LNM35 suggest mimicry of inflammatory cells in metastasis. Oncogene 2001; 20: 4228–34PubMedCrossRefGoogle Scholar
  105. 105.
    Singh B, Berry J, Shoher A, et al. COX-2 overexpression increases motility and invasion of breast cancer cells. Int J Radiat Oncol 2005; 26: 1393–9Google Scholar
  106. 106.
    Kakiuchi Y, Tsuji S, Tsujii M, et al. Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis. Cancer Res 2002; 62: 1567–72PubMedGoogle Scholar
  107. 107.
    Niki T, Kohno T, Iba S, 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 2002; 160: 1129–41PubMedCrossRefGoogle Scholar
  108. 108.
    Fulton AM. Interactions of natural effector cells and prostaglandins in the control of metastasis. J Natl Cancer Inst 1987; 78: 735–41PubMedGoogle Scholar
  109. 109.
    Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–11PubMedGoogle Scholar
  110. 110.
    Tsubouchi Y, Mukai S, Kawahito Y, et al. Meloxicam inhibits the growth of non-small cell lung cancer. Anticancer Res 2000; 20: 2867–72PubMedGoogle Scholar
  111. 111.
    Gee J, Lee I, Fischer S, et al. COX-2 selective inhibitor celecoxib induces growth inhibition and apoptosis in bladder carcinoma. Proc Am Assoc Cancer Res 2002; 43: 643–4Google Scholar
  112. 112.
    Zweifel B, Ornberg R, Woerner M, et al. Inhibition of prostaglandins by celecoxib results in suppression of tumor growth and reduces VEGF level in human head and neck xenograft model [abstract]. Proc Am Assoc Cancer Res 2002; 43: 77Google Scholar
  113. 113.
    Yazawa K, NH T, Kitayama J, et al. Selective inhibition of cyclooxygenase-2 inhibits colon cancer cell adhesion to extracellular matrix by decreased expression of beta1 integrin. Cancer Sci 2005; 96: 93–9PubMedCrossRefGoogle Scholar
  114. 114.
    Qadri S, Wang J, Coffey J, et al. Surgically induced accelerated local and distant tumor growth is significantly attenuated by selective COX-2 inhibition. Ann Thorac Surg 2005; 79: 990–5PubMedCrossRefGoogle Scholar
  115. 115.
    Eling TE, Curtis JF. Xenobiotic metabolism by prostaglandin H synthase. Pharmacol Ther 1992; 53: 261–73PubMedCrossRefGoogle Scholar
  116. 116.
    Marnett L. Generation of mutagens during arachidonic acid metabolism. Cancer Metastasis Rev 1994; 13 (3–4): 303–8PubMedCrossRefGoogle Scholar
  117. 117.
    Prescott S, White R. Self-promotion? Intimate connections between APC and prostaglandin H synthase-2. Cell 1996; 87: 783–6PubMedCrossRefGoogle Scholar
  118. 118.
    Wiese FW, Thompson PA, Kadlubar FF. Carcinogen substrate specificity of human COX-1 and COX-2. Carcinogenesis 2001; 22: 5–10PubMedCrossRefGoogle Scholar
  119. 119.
    Smith M-L, Hawcroft G, Hull MA. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J Cancer 2000; 36: 664–74PubMedCrossRefGoogle Scholar
  120. 120.
    Watson AJ. Chemopreventive effects of NSAIDs against colorectal cancer: regulation of apoptosis and mitosis by COX-1 and COX-2. Histol Histopathol 1998; 13: 591–7PubMedGoogle Scholar
  121. 121.
    Soo R, Putti T, Tao Q, et al. Overexpression of cyclooxygenase-2 in nasopharyngeal carcinoma and association with epidermal growth factor receptor expression. Arch Otolaryngol Head Neck Surg 2005; 131: 147–52PubMedCrossRefGoogle Scholar
  122. 122.
    Diaz-Cruz ES, Shapiro CL, Brueggemeier RW. Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells. J Clin Endocrinol Metab 2005; 90: 2563–70PubMedCrossRefGoogle Scholar
  123. 123.
    Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995; 83: 493–501PubMedCrossRefGoogle Scholar
  124. 124.
    Dempke W, Rie C, Grothey A, et al. Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol 2001; 127: 411–7PubMedCrossRefGoogle Scholar
  125. 125.
    Sun Y, Sinicrope FA. Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells. Mol Cancer Ther 2005; 4: 51–9PubMedGoogle Scholar
  126. 126.
    Form DM, Auerbach R. PGE2 and angiogenesis. Proc Soc Exp Biol Med 1983; 172: 214–8PubMedGoogle Scholar
  127. 127.
    Ziche M, Jones J, Gullino PM. Role of prostaglandin E1 and copper in angiogenesis. J Natl Cancer Inst 1982; 69: 475–82PubMedGoogle Scholar
  128. 128.
    Williams CS, Tsujii M, Reese J, et al. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 2000; 105: 1589–94PubMedCrossRefGoogle Scholar
  129. 129.
    Majima M, Hayashi I, Muramatsu M, et al. Cyclo-oxygenase-2 enhances basic fibroblast growth factor-induced angiogenesis through induction of vascular endothelial growth factor in rat sponge implants. Br J Pharmacol 2000; 130: 641–9PubMedCrossRefGoogle Scholar
  130. 130.
    Rak J, Filmus J, Kerbel RS. Reciprocal paracrine interactions between tumour cells and endothelial cells: the ‘angiogenesis progression’ hypothesis. Eur J Cancer 1996; 32A: 2438–50PubMedCrossRefGoogle Scholar
  131. 131.
    Liu J, Yu H, JP Y, et al. Overexpression of cyclooxygenase-2 in gastric cancer correlates with the high abundance of vascular endothelial growth factor-C and lymphatic metastasis. Med Oncol 2005; 2: 389–97CrossRefGoogle Scholar
  132. 132.
    Imada T, Matsuoka J, Nobuhisa T, et al. COX-2 induction by heparanase in the progression of breast cancer. Int J Mol Med 2006; 17: 221–8PubMedGoogle Scholar
  133. 133.
    Okawa T, Naomoto Y, Nobuhisa T, et al. Heparanase is involved in angiogenesis in esophageal cancer through induction of cyclooxygenase-2. Clin Cancer Res 2005; 11: 7995–8005PubMedCrossRefGoogle Scholar
  134. 134.
    Toyoki H, Fujimoto J, Sato E, et al. Clinical implications of expression of cyclooxygenase-2 related to angiogenesis in uterine endometrial cancers. Ann Oncol 2005; 16: 51–5PubMedCrossRefGoogle Scholar
  135. 135.
    Raspollini M, Susini T, Amunni G, et al. COX-2, c-KIT and HER-2/neu expression in uterine carcinosarcomas: prognostic factors or potential markers for targeted therapies? Gynecol Oncol 2005; 96: 159–67PubMedCrossRefGoogle Scholar
  136. 136.
    Sheehan K, Steele C, Sheahan K, et al. Association between cyclooxygenase-2-expressing macrophages, ulceration and microvessel density in colorectal cancer. Histopathology 2005; 46: 287–95PubMedCrossRefGoogle Scholar
  137. 137.
    Eibl G, Takata Y, Boros LG, et al. Growth stimulation of COX-2-negative pancreatic cancer by a selective COX-2 inhibitor. Cancer Res 2005; 65: 982–90PubMedGoogle Scholar
  138. 138.
    Milas L, Furuta Y, Hunter N, et al. Dependence of indomethacin-induced potentiation of murine tumor radioresponse on tumor host immunocompetence. Cancer Res 1990; 50: 4473–7PubMedGoogle Scholar
  139. 139.
    Milas L, Kishi K, Hunter N, et al. Enhancement of tumor response to γ-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst 1999; 91: 1501–4PubMedCrossRefGoogle Scholar
  140. 140.
    Leahy KM, Ornberg RL, Wang Y, et al. Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 2002; 62: 625–31PubMedGoogle Scholar
  141. 141.
    Dicker A, Williams T, Grant D. Targeting angiogenic processes by combination rofecoxib and ionizing radiation. Am J Clin Oncol 2001; 24: 438–42PubMedCrossRefGoogle Scholar
  142. 142.
    Haas AR, Sun J, Vachani A, et al. Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine. Clin Cancer Res 2006; 12: 214–22PubMedCrossRefGoogle Scholar
  143. 143.
    Brunda M, Herberman R, Holden H. Inhibition of murine natural killer cell activity by prostaglandins. J Immunol 1980; 124: 2682–7PubMedGoogle Scholar
  144. 144.
    Leung KH, Mihich E. Prostaglandin modulation of development of cell-mediated immunity in culture. Nature 1980; 288: 597–600PubMedCrossRefGoogle Scholar
  145. 145.
    Fulton AM, Levy JG. The possible role of prostaglandins in mediating immune suppression by nonspecific T suppressor cells. Cell Immunol 1980; 52: 29–37PubMedCrossRefGoogle Scholar
  146. 146.
    Kambayashi T, Alexander HR, Fong M, et al. Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10. J Immunol 1995; 154: 3383–90Google Scholar
  147. 147.
    Huang M, Stolina M, Sharma S, et al. Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production. Cancer Res 1998; 58: 1208–16PubMedGoogle Scholar
  148. 148.
    Stolina M, Sharma S, Lin Y, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 2000; 164: 361–70PubMedGoogle Scholar
  149. 149.
    Ohno Y, Ohno S, Suzuki N, et al. Role of cyclooxygenase-2 in immunomodulation and prognosis of endometrial carcinoma. Int J Cancer 2005; 114: 696–701PubMedCrossRefGoogle Scholar
  150. 150.
    Sharma S, Yang S-C, Zhu L, et al. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer. Cancer Res 2005; 65: 5211–20PubMedCrossRefGoogle Scholar
  151. 151.
    Kundu N, Walser T, Ma X, et al. Cyclooxygenase inhibitors modulate NK activities that control metastatic disease. Cancer Immunol Immunother 2005; 54: 981–97PubMedCrossRefGoogle Scholar
  152. 152.
    Milas L, Nishiguchi I, Hunter N, et al. Radiation protection against early and late effects of ionizing irradiation by the prostaglandin inhibitor indomethacin. Adv Space Res 1992; 12: 265–71PubMedCrossRefGoogle Scholar
  153. 153.
    Maier TJ, Schilling K, Schmidt R, et al. Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Biochem Pharmacol 2004; 67: 1469–78PubMedCrossRefGoogle Scholar
  154. 154.
    Patel MI, Subbaramaiah K, Du B, et al. Celecoxib inhibits prostate cancer growth: Evidence of a cyclooxygenase-2-independent mechanism. Clin Cancer Res 2005; 11: 1999–2007PubMedCrossRefGoogle Scholar
  155. 155.
    Williams CS, Watson AJM, Sheng H, et al. Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 2000; 60: 6045–51PubMedGoogle Scholar
  156. 156.
    Kardosh A, Soriano N, Liu Y-T, et al. Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib. Blood 2005; 106: 4330–8PubMedCrossRefGoogle Scholar
  157. 157.
    Lou J, Fatima N, Xiao Z, et al. Proteomic profiling identifies cyclooxygenase-2-independent global proteomic changes by celecoxib in colorectal cancer cells. Cancer Epidemiol Biomarkers Prev 2006; 15: 1598–606PubMedCrossRefGoogle Scholar
  158. 158.
    Ostrowski J, Wocial T, Skurzak H, et al. Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors? Br J Cancer 2003; 88: 1143–51PubMedCrossRefGoogle Scholar
  159. 159.
    Hanson WR. Eicosanoid-induced radioprotection and chemoprotection: laboratory studies and clinical applications. In: Bump EA, Malaker K, editors. Radioprotectors: chemical, biological and clinical perspectives. Boca Raton (FL): CRC Press, 1998: 197–221Google Scholar
  160. 160.
    Milas L, Hunter NR, Mason KA, et al. Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel. Cancer Res 1995; 55: 3564–8PubMedGoogle Scholar
  161. 161.
    van Buul PP, van Duyn-Goedhart A, Sankaranarayanan K. In vivo and in vitro radioprotective effects of the prostaglandin E1 analogue misoprostol in DNA repair-proficient and -deficient rodent cell systems. Radiat Res 1999; 152: 398–403PubMedCrossRefGoogle Scholar
  162. 162.
    Hanson W, Thomas C. 16, 16-dimethyl prostaglandin E2 increases survival of murine intestinal stem cells when given before photon radiation. Radiat Res 1983; 96: 393–8PubMedCrossRefGoogle Scholar
  163. 163.
    Hanson W, Geng L, Malkinson F. Prostaglandin-induced protection from radiation or doxorubicin is tissue specific and dependent upon receptor expression. Tenth International Congress of Radiation Research. Wurzburg, Germany; 1995: 435Google Scholar
  164. 164.
    Geng L, Hanson WR, Malkinson FD. Topical or systemic 16, 16 dm prostaglandin E2 or WR-2721 (WR-1065) protects mice from alopecia after fractionated irradiation. Int J Radiat Biol 1992; 61: 533–7PubMedCrossRefGoogle Scholar
  165. 165.
    van Buul PP, van Duyn-Goedhart A, de Rooij DG, et al. Differential radioprotective effects of misoprostol in DNA repair-proficient and -deficient or radiosensitive cell systems. Int J Radiat Biol 1997; 71: 259–64PubMedCrossRefGoogle Scholar
  166. 166.
    Zaffaroni N, Villa R, Orlandi L, et al. Differential effect of 9 beta-chloro-16, 16-dimethyl prostaglandin E2 (nocloprost) on the radiation response of human normal fibroblasts and colon adenocarcinoma cells. Radiat Res 1993; 135: 88–92PubMedCrossRefGoogle Scholar
  167. 167.
    Houchen CW, Stenson WF, Cohn SM. Disruption of cyclooxygenase-1 gene results in an impaired response to radiation injury. Am J Physiol Gastrointest Liver Physiol 2000; 279: G858–65PubMedGoogle Scholar
  168. 168.
    Furuta Y, Hunter N, Barkley T, et al. Increase in radioresponse of murine tumors by treatment with indomethacin. Cancer Res 1988; 48: 3008–13PubMedGoogle Scholar
  169. 169.
    Kishi K, Petersen S, Petersen C, et al. Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res 2000; 60: 1326–31PubMedGoogle Scholar
  170. 170.
    Petersen C, Petersen S, Milas L, et al. Human glioma cell radiosensitization by a selective COX-2 inhibitor. Clin Cancer Res 2000; 6: 2513–20PubMedGoogle Scholar
  171. 171.
    Pyo H, Choy H, Amorino GP, et al. A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2. Clin Cancer Res 2001; 7: 2998–3005PubMedGoogle Scholar
  172. 172.
    Davis G, Martin L-A, Sacks N, et al. Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention. Ann Oncol 2002; 13: 669–78CrossRefGoogle Scholar
  173. 173.
    Amirghahari N, Harrison L, Smith M, et al. NS 398 radiosensitizes an HNSCC cell line by possibly inhibiting radiation-induced expression of COX-2. Int J Radiat Oncol Biol Phys 2003; 57: 1405–12PubMedCrossRefGoogle Scholar
  174. 174.
    Wen B, Deutsch E, Eschwege P, et al. Cyclooxygenase-2 inhibitor NS398 enhances antitumor effect of irradiation on hormone refractory human prostate carcinoma cells. J Urol 2003; 170: 2036–9PubMedCrossRefGoogle Scholar
  175. 175.
    Milas L. Cyclooxygenase-2 (COX-2) enzyme inhibitors and radiotherapy. Am J Clin Oncol 2003; 26: S66–9PubMedGoogle Scholar
  176. 176.
    Raju U, Nakata E, Yang P, et al. In vitro enhancement of tumor cell radiosensitivity by a selective inhibitor of cyclooxygenase-2 enzyme: mechanistic considerations. Int J Radiat Oncol Biol Phys 2002; 54: 886–94PubMedCrossRefGoogle Scholar
  177. 177.
    Raju U, Aroga H, Dittmann K. Inhibition of DNA repair as a mechanism of enhanced radioresponse of head and neck carcinoma cells by a selective cyclooxygenase-2 inhibitor, celecoxib. Int J Radiat Oncol Biol Phys 2005; 63: 520–8PubMedCrossRefGoogle Scholar
  178. 178.
    Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockade of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999; 59: 3374–8PubMedGoogle Scholar
  179. 179.
    Gorski DH, Mauceri HJ, Salloum RM, et al. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res 1998; 58: 5686–9PubMedGoogle Scholar
  180. 180.
    Teicher BA, Bump EA, Palayoor ST, et al. Signal transduction inhibitors as modifiers of radiation therapy in human prostate carcinoma xenografts. Radiat Oncol Investig 1996; 4: 221–30CrossRefGoogle Scholar
  181. 181.
    Zhang X, Chen Z, Choe MS, et al. Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model. Clin Cancer Res 2005; 11: 6261–9PubMedCrossRefGoogle Scholar
  182. 182.
    Vallbohmer D, Zhang W, Gordon M, et al. Molecular determinants of cetuximab efficacy. J Clin Oncol 2005; 23: 3536–44PubMedCrossRefGoogle Scholar
  183. 183.
    Teicher BA, Holden SA, Dupuis NP, et al. Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma. Breast Cancer Res Treat 1995; 36: 227–36PubMedCrossRefGoogle Scholar
  184. 184.
    Mason KA, Kishi K, Hunter N, et al. Effect of docetaxel on the therapeutic ratio of fractionated radiotherapy in vivo. Clin Cancer Res 1999; 5: 4191–8PubMedGoogle Scholar
  185. 185.
    Li L, Rojiani A, Siemann DW. Targeting the tumor vasculature with combretastatin A-4 disodium phosphate: effects on radiation therapy. Int J Radiat Oncol Biol Phys 1998; 42: 335–63Google Scholar
  186. 186.
    Milas L, Mason K, Hunter N, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 2000; 6: 701–8PubMedGoogle Scholar
  187. 187.
    Haimovitz-Friedman A, Vlodavsky I, Chaudhuri A, et al. Autocrine effects of fibroblast growth factor in repair of radiation damage in endothelial cells. Cancer Res 1991; 51: 2552–8PubMedGoogle Scholar
  188. 188.
    Steinauer KK, Gibbs I, Ning S, et al. Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cells. Int J Radiat Oncol Biol Phys 2000; 48: 325–8PubMedCrossRefGoogle Scholar
  189. 189.
    Torrance CJ, Jackson PE, Montgomery E, et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000; 6: 1024–8PubMedCrossRefGoogle Scholar
  190. 190.
    Harari PM, Huang SM. Radiation response modification following molecular inhibition of epidermal growth factor receptor signalling. Semin Radiat Oncol 2001; 11: 281–90PubMedCrossRefGoogle Scholar
  191. 191.
    Parashar B, Latha Shankar S, O’Guin K, et al. Inhibition of human neuroblastoma cell growth by CAY10404, a highly selective Cox-2 inhibitor. J Neurooncol 2005; 71: 141–8PubMedCrossRefGoogle Scholar
  192. 192.
    Altorki NK, Port JL, Zhang F, et al. Chemotherapy induces the expression of cyclooxygenase-2 in non-small cell lung cancer. Clin Cancer Res 2005; 11: 4191–7PubMedCrossRefGoogle Scholar
  193. 193.
    Subbaramaiah K, Hart JC, Norton L, et al. Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2._Evidence for involvement of ERK 1/2 and p38 mitogen-activated protein kinase pathways. J Biol Chem 2000; 275: 14838–45PubMedCrossRefGoogle Scholar
  194. 194.
    Hida T, Kozaki K-I, Ito H, et al. Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a selective cyclooxygenase 2 inhibitor, JTE-522, and conventional anticancer agents. Clin Cancer Res 2002; 8: 2443–7PubMedGoogle Scholar
  195. 195.
    Duffy C, Elliott C, O’Connor R, et al. Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs). Eur J Cancer 1998; 34: 1250–9PubMedCrossRefGoogle Scholar
  196. 196.
    Manson MM, Holloway KA, Howells LM, et al. Modulation of signal-transduction pathways by chemopreventive agents. Biochem Soc Trans 2000; 28: 7–12PubMedGoogle Scholar
  197. 197.
    Trifan OC, Durham WF, Salazar VS, et al. Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11. Cancer Res 2002; 62: 5778–84PubMedGoogle Scholar
  198. 198.
    Nakata E, Mason K, Hunter N, et al. Potentiation of tumor response to radiation or chemoradiation by selective cyclooxygenase-2 enzyme inhibitors. Int J Radiat Oncol Biol Phys 2004; 58: 369–75PubMedCrossRefGoogle Scholar
  199. 199.
    Altorki NK, Keresztes RS, Port JL, et al. Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to pre-operative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 2003; 21: 2645–50PubMedCrossRefGoogle Scholar
  200. 200.
    Parel V, Dunn M, Sorokin A. Regulation of MDR-2 (P-glycoprotein) by cyclooxygenase-2. J Biol Chem 2002; 277: 38915–20CrossRefGoogle Scholar
  201. 201.
    Ratnasinghe D, Daschner P, Anver M, et al. Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; is chemoprevention against multidrug resistance possible? Anticancer Res 2001; 21: 2141–7PubMedGoogle Scholar
  202. 202.
    Kang H-K, Lee E, Pyo H, et al. Cyclooxygenase-independent down-regulation of multidrug resistance-associated protein-1 expression by celecoxib in human lung cancer cells. Mol Cancer Ther 2005; 4: 1358–63PubMedCrossRefGoogle Scholar
  203. 203.
    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: 1247–55PubMedCrossRefGoogle Scholar
  204. 204.
    Cleland LG, James MJ, Stamp LK, et al. COX-2 inhibition and thrombotic tendency: a need for surveillance. Med J Aust 2001; 175: 214–7PubMedGoogle Scholar
  205. 205.
    Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954–9PubMedCrossRefGoogle Scholar
  206. 206.
    Howes LG, Kram H. Selective cyclo-oxygenase-2 inhibitors and myocardial infarction: how strong is the link? Drag Saf 2002; 25: 829–35CrossRefGoogle Scholar
  207. 207.
    Liao Z, Komaki R, Milas L, et al. A phase I clinical trial of thoracic radiotherapy and concurrent celecoxib for patients with unfavorable performance status inoperable/unresectable non-small cell lung cancer. Clin Cancer Res 2005; 11: 3342–8PubMedCrossRefGoogle Scholar
  208. 208.
    Csiki I, Dang T, Gonzalez A. Cyclooxygenase-2 (COX-2) inhibition + docetaxel (Txt) in recurrent non-small cell lung cancer (NSCLC): preliminary results of a phase II trial (THO-0054) [abstract no. 1187]. Proc Am Soc Clin Oncol 2002; 21: 297aGoogle Scholar
  209. 209.
    Csiki I, Morrow JD, Sandier A, et al. Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Cancer Res 2005; 11: 6634–40PubMedCrossRefGoogle Scholar
  210. 210.
    Blanke C, Benson A, Dragovich T, et al. A phase II trial of celexoxib (CB), irinotecan (I), 5-fluorouracil (5FU), and leucovorin (LCV) in patients (pts) with unresectable or metastatic colorectal cancer (CRC) [abstract]. Proc Am Soc Clin Oncol 2002; 21: 127Google Scholar
  211. 211.
    Gasparini G, Gattuso D, Morabito A, et al. Combined therapy with weekly Irinotecan, infusional 5-fluorouracil and the selective COX-2 inhibitor rofecoxib is a safe and effective second-line treatment in metastatic colorectal cancer. Oncologist 2005; 10: 710–7PubMedCrossRefGoogle Scholar
  212. 212.
    Sweeney C, Seitz D, Ansari R, et al. A phase II trial of irinotecan (I), 4-fluorouracil (F), leucovorin (L) (IFL), celecoxib and glutamine as first line therapy for advanced colorectal cancer: a Hoosier Oncology Group study [abstract]. Proc Am Soc Clin Oncol 2002; 21: 105bGoogle Scholar
  213. 213.
    Lin E, Morris J, Chau N, et al. Celecoxib attenuated capecitabine induced hand-and-foot syndrome (HFS) and diarrhea and improved time to tumor progression in metastatic colorectal cancer (MCRC) [abstract]. Proc Am Soc Clin Oncol 2002; 21: 138bGoogle Scholar
  214. 214.
    Tuynman J, Buskens C, Kemper K, et al. Neoadjuvant selective COX-2 inhibition down-regulates important oncogenic pathways in patients with esophageal adenocarcinoma. Ann Surg 2005; 242: 840–9PubMedCrossRefGoogle Scholar
  215. 215.
    Govindan R, McLeod H, Mantravadi P, et al. Cisplatin, fluorouracil, celecoxib, and RT in resectable esophageal cancer: preliminary results. Oncology 2004; 18: 18–21PubMedGoogle Scholar
  216. 216.
    Uchida K, Schneider S, Yochim JM, et al. Intratumoral COX-2 gene expression is a predictive factor for colorectal cancer response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2005; 11: 3363–8PubMedCrossRefGoogle Scholar
  217. 217.
    Ferrari V, Valcamonico F, Amoroso V, et al. Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol 2006; 57: 185–90PubMedCrossRefGoogle Scholar
  218. 218.
    Bertagnoli M, Eagle C, Zauber A, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873–84CrossRefGoogle Scholar
  219. 219.
    Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95PubMedCrossRefGoogle Scholar
  220. 220.
    Bresalier RS, Sandier RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102PubMedCrossRefGoogle Scholar
  221. 221.
    Connolly E, Harmey J, O’Grady T, et al. Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthopedic model of breast cancer. Br J Cancer 2002; 87: 231–7PubMedCrossRefGoogle Scholar
  222. 222.
    Kundu N, Fulton AM. Selective cyclooxygenase (COX)-l or COX-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res 2002; 62: 2343–6PubMedGoogle Scholar
  223. 223.
    Takahashi Y, Kawahara F, Noguchi M, et al. Activation of matrix metalloproteinase-2 in human breast cancer cells over-expressing cyclooxygenase-1 or-2. FEBS Letters 1999; 460: 145–8PubMedCrossRefGoogle Scholar
  224. 224.
    Sivula S, Talvensaari-Mattila A, Lundin J, et al. Association of cyclooxygenase-2 and matrix metalloproteinase-2 expression in human breast cancer. Breast Cancer Res Treat 2005; 89: 215–20PubMedCrossRefGoogle Scholar
  225. 225.
    Howe LR, Subbaramaiah K, Patel J, et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 2002; 62: 5405–7PubMedGoogle Scholar
  226. 226.
    Brueggemeier RW, Quinn AL, Parrett ML, et al. Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Lett 1999; 140: 27–35PubMedCrossRefGoogle Scholar
  227. 227.
    Bundred N, Barnes N. Potential use of COX-2-aromatase inhibitor combinations in breast cancer. Br J Cancer 2005; 93: S10–15PubMedCrossRefGoogle Scholar
  228. 228.
    Chow L, Toi M. Neoadjuvant celexoxib and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) for the treatment of locally advanced breast cancer (LABC) [abstract]. Proc Am Soc Clin Oncol 2003; 22: 327Google Scholar
  229. 229.
    Dirix L, Ignacio J, Nag S, et al. Final results from an open-label, multicenter, controlled study of exemestane +/−celecoxib in postmenopausal women with advanced breast cancer (ABC) progressed on tamoxifen (T) [abstract]. Proc Am Soc Clin Oncol 2003; 22: 77CrossRefGoogle Scholar
  230. 230.
    Gasparini G, Longo R, Sarmiento R, et al. Inhibitors of cyclooxygenase 2: a new class of anticancer agents? Lancet Oncol 2003; 4: 605–15PubMedCrossRefGoogle Scholar
  231. 231.
    Arun B, Goss P. The role of COX-2 inhibition in breast cancer treatment and prevention. Semin Oncol 2004; 31: 22–9PubMedCrossRefGoogle Scholar
  232. 232.
    Spieth K, Kaufmann R, Gille J. Metronomic oral low-dose terosulfan chemotherapy combined with clyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study. Cancer Chemother Pharmacol 2003; 377-82Google Scholar
  233. 233.
    Reardon D, Quinn J, Vredenburgh J, et al. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer 2005; 103: 329–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Division of Radiation Oncology, Unit 97University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Experimental Radiation OncologyUniversity of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations