Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1996 Apr;122(4):219–222. doi: 10.1007/BF01209649

Suppression of azoxymethane-induced aberrant crypt foci in rat colon by nimesulide, a selective inhibitor of cyclooxygenase 2

Mami Takahashi 1, Masato Fukutake 1, Shigeru Yokota 1, Kaori Ishida 1, Keiji Wakabayashi 1, Takashi Sugimura 1,✉
PMCID: PMC12201058  PMID: 8601574

Abstract

Non-steroidal anti-inflammatory drugs, such as piroxicam and sulindac, are known to inhibit development of aberrant crypt foci (ACF) and cancer in the colon. However, these agents cause gastrointestinal side-effects. Nimesulide is a selective inhibitor of cyclooxygenase 2 and has been shown to have a more potent anti-inflammatory action than piroxicam, but be less ulcerogenic and, therefore, a potentially more useful chemopreventive agent. To assess this possibility the inhibitory effects of nimesulide on the formation of ACF induced by azoxymethane in rat colon were investigated, and compared with those of piroxicam and sulindac. Male F344 rats were treated s.c. with 15 mg/kg body weight azoxymethane once a week for 2 weeks and given 50, 100 or 200 ppm nimesulide, 200 ppm piroxicam, or 200 ppm sulindac in their diet from the day before the first carcinogen treatment until the end of the experiment at week 4. At this time, nimesulide at doses of 50, 100 and 200 ppm had reduced the numbers of azoxymethane-induced ACF to 75%, 71% and 65% respectively compared to the control. The number of azoxymethane-induced ACF per colon in the group given 200 ppm nimesulide was almost the same as in those given 200 ppm piroxicam, and lower than that in the group given 200 ppm sulindac. These results suggest that nimesulide, a selective cyclooxygenase 2 inhibitor, warrants attention as a candidate for chemopreventive agent with low toxicity, active against colon carcinogenesis.

Key words: Nimesulide, Cyclooxygenase 2, Aberrant crypt foci, Azoxymethane, Rat colon carcinogenesis

Abbreviations

ACF

aberrant crypt foci

COX

cyclooxygenase

NSAID

non-steroidal anti-inflammatory drugs

Footnotes

The work was supported by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan, and the Ministry of Health and Welfare for the Second-Term Comprehensive 10-Year Strategy for Cancer Control, Japan, and a grant from the Bristol-Myers Squibb Foundation

References

  1. Bird RP (1987) Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 37: 147–151 [DOI] [PubMed] [Google Scholar]
  2. Böttcher I, Schweizer A, Glatt M, Werner H (1987) A sulphonamido-indanone derivative CPG 28237 (ZK 34228), a novel nonsteroidal anti-inflammatory agent without gastro-intestinal ulcerogenicity in rats. Drugs Exp Clin Res 13: 237–245 [PubMed] [Google Scholar]
  3. Broder S (1993) Perspectives on cancer in Japan and the United States. Jpn J Cancer Res 84: 821–830 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cipollini F, Mecozzi V, Altilia F (1989) Endoscopic assessment of the effects of nimesulide on the gastric mucosa: comparison with indomethacin. Curr Ther Res 45: 1042–1048 [Google Scholar]
  5. Copeland RA, Williams JM, Giannaras J, Nurnberg S Covington M, Pinto D, Pick S, Trzaskos JM (1994) Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase. Proc Natl Acad Sci USA 91: 11202–11206 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DuBois RN, Awad J, Morrow J, Roberts LJ, II, Bishop R (1994) Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-α and phorbol ester. Clin Invest 93: 493–498 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107: 1183–1188 [DOI] [PubMed] [Google Scholar]
  8. Kargman SL, O'Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S (1995) Expression of prostaglandin G/H synthase-1 and-2 protein in human colon cancer. Cancer Res 55: 2556–2559 [PubMed] [Google Scholar]
  9. Labyle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P (1991) Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101: 635–639 [DOI] [PubMed] [Google Scholar]
  10. Langman MJS (1989) Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use. Gastroenterology 96: 640–646 [DOI] [PubMed] [Google Scholar]
  11. Masferrer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, Isakson PC, Seibert K (1994) Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci USA 91: 3228–3232 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Meade EA, Smith WL, DeWitt DL (1993) Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 268: 6610–6614 [PubMed] [Google Scholar]
  13. Mereto E, Frencia L, Ghia M (1994) Effect of aspirin on incidence and growth of aberrant crypt foci induced in the rat colon by 1,2-dimethylhydrazine. Cancer Lett 76: 5–9 [DOI] [PubMed] [Google Scholar]
  14. Pereira MA, Barnes LH, Rassman VL, Kelloff GV, Steele VE (1994) Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents. Carcinogenesis 15: 1049–1054 [DOI] [PubMed] [Google Scholar]
  15. Pretlow TP, Barrow BJ, Ashton WS, O'Riordan MA, Pretlow TG, Jurcisek JA, Stellato TA (1991) Aberrant crypts: putative preneoplastic foci in human colonic mucosa. Cancer Res 51: 1564–1567 [PubMed] [Google Scholar]
  16. Rao CV, Rivenson A, Simi B, Zang E, Kelloff G, Steele V, Reddy BS (1995) Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent. Cancer Res 55: 1464–1472 [PubMed] [Google Scholar]
  17. Reddy BS, Maruyama H, Kelloff G (1987) Dose-related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteroidal antiinflammatory drugs, during different stages of rat colon tumor development. Cancer Res 47: 5340–5346 [PubMed] [Google Scholar]
  18. Reddy BS, Tokumo K, Kulkarni N, Aligia C, Kelloff G (1992) Inhibition of colon carcinogenesis by prostaglandin synthesis inhibitors and related compounds. Carcinogenesis 13: 1019–1023 [DOI] [PubMed] [Google Scholar]
  19. Reddy BS, Rao CV, Rivenson A, Kelloff G (1993) Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats. Carcinogenesis 14: 1493–1497 [DOI] [PubMed] [Google Scholar]
  20. Reitz DB, Li JJ, Norton MB, Reinhard EJ, Collins JT, Anderson GD, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Isakson PC (1994) Selective cyclooxygenase inhibitors: novel 1,2-diaryl-cyclopentenes are potent and orally active COX-2 inhibitors. J Med Chem 37: 3878–3881 [DOI] [PubMed] [Google Scholar]
  21. Rigas B, Goldman IS, Levine L (1993) Altered eicosanoid levels in human colon cancer. J Lab Clin Med 122: 518–523 [PubMed] [Google Scholar]
  22. Roncucci L, Stamp D, Medline A, Cullen JB, Bruce WR (1991) Identification and quantification of aberrant crypt foci and microadenomas in the human colon. Hum Pathol 22: 287–294 [DOI] [PubMed] [Google Scholar]
  23. Swingle KF, Moore GGI (1984) Preclinical pharmacological studies with nimesulide. Drugs Exp Clin Res 10: 587–597 [Google Scholar]
  24. Takahashi M, Minamoto T, Yamashita N, Yazawa K, Sugimura T, Esumi H (1993) Reduction in formation and growth of 1,2-dimethylhydrazine-induced aberrant crypt foci in rat colon by docosahexaenoic acid. Cancer Res 53: 2786–2789 [PubMed] [Google Scholar]
  25. Takahashi S, Ogawa K, Ohshima H, Esumi H, Ito N, Sugimura T (1991) Induction of aberrant crypt foci in the large intestine of F344 rats by oral administration of 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine. Jpn J Cancer Res 82: 135–137 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Taniguchi Y, Ikesue A, Yokoyama K, Noda K, Debuchi H, Nakamura T, Toda A, Shimeno H (1995) Selective inhibition by nimesulide, a novel non-steroidal anti-inflammatory drug, with prostaglandin endoperoxide synthase-2 activity in-vitro. Pharm Sci 1: 173–175 [Google Scholar]
  27. Thun MJ, Namboodiri MM, Heath CW Jr (1991) Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325: 1593–1596 [DOI] [PubMed] [Google Scholar]
  28. Tofanetti O, Casciarri I, Cipolla PV, Cazzulani P, Omini C (1989) Effect of nimesulide on cyclo-oxygenase activity in rat gastric mucosa and inflammatory exudate. Med Sci Res 17: 745–746 [Google Scholar]
  29. Tudek B, Bird RP, Bruce WR (1989) Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods. Cancer Res 49: 1236–1240 [PubMed] [Google Scholar]
  30. Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL (1991) Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 88: 2692–2696 [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES