Skip to main content
SpringerLink
Log in

Aspirin, but Not Sodium Salicylate, Indomethacin, or Nabumetone, Reversibly Suppresses 1,2-Dimethylhydrazine-Induced Colonic Aberrant Crypt Foci in Rats

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The aim of this study was to determine ifselective inhibition of cyclooxygenase isozymes affectsthe initiation of carcinogen-induced colon cancer usingaberrant crypt foci (ACF) as a surrogate biomarker. Male Sprague-Dawley rats (18 per group) weregiven single subcutaneous injections of saline (4ml/kg), aspirin (50 mg/kg body wt) sodium salicylate (50mg/kg), indomethacin (4 mg/kg), nabumetone (100 mg/kg), or 16,16-dimethyl-prostaglandin E2(50 mg/kg) for three days. On day 4, 12 rats per groupwere given a subcutaneous injection 2 of1,2-dimethylhydrazine (12 mg base/kg body wt) and sixrats per group received vehicle alone (4 ml/kg) every week for eightweeks, after which drug treatment ceased. Control andsix carcinogen-treated rats per group were killed atthis time and the remaining six rats per group killed 22 weeks later. Colons were scored for ACFnumber and size. Only aspirin caused a significantreduction in total ACF and ACF formation at the earlytime point, but at the later time, there were nosignificant differences between groups. ACF from alltreatment groups increased in size at similar rates atboth time points. Thus, only aspirin demonstrated asignificant, although reversible, suppression ofcarcinogen-induced ACF. Possible mechanisms of action and theclinical implications of aspirin chemoprevention arediscussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Thun MJ: Aspirin, NSAIDs, and digestive tract cancers. Cancer Metast Rev 13:269-277, 1994

    Google Scholar 

  2. Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, Speizer FE: Aspirin and the risk of colorectal cancer in women. N Engl J Med 333:609-614, 1995

    Google Scholar 

  3. Reddy BS, Rao CV, Rivenson A, Kelloff G: Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats. Carcinogenesis 14:1493-1497, 1993

    Google Scholar 

  4. Craven PA, DeRubertis FR: Effects of aspirin on 1,2-dimethylhydrazine-induced colonic carcinogenesis. Carcinogenesis 13:541-546, 1992

    Google Scholar 

  5. Meade EA, Smith WL, DeWitt DL: Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem 268:6610-6614, 1993

    Google Scholar 

  6. Marnett LJ: Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 52:5575-5589, 1992

    Google Scholar 

  7. Lecomte M, Laneuville O, Ji C, DeWitt DL, Smith WL: Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. J Biol Chem 269:13207-13215, 1994

    Google Scholar 

  8. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, Dubois RN: Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107:1183-1188, 1994

    Google Scholar 

  9. Laneuville O, Breuer DK, DeWitt DL, Hla T, Funk CD, Smith WL: Differential inhibition of human prostaglandin endoperoxide synthases-1 and-2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 271:927-934, 1994

    Google Scholar 

  10. Qiao L, Kozoni V, Tsioulias GJ, Koutsos MI, Hanif R, Shiff NSJ, Rigas B: Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. Biochim Biophys Acta 1258:215-223, 1995

    Google Scholar 

  11. Pretlow TP: Aberrant crypt foci and K-ras mutations: Earliest recognized players or innocent bystanders in colon carcinogenesis. Gastroenterology 108:600-609, 1995

    Google Scholar 

  12. Yamashita N, Minamoto T, Ochiai A, Onda M, Esumi H: Frequent and characteristic K-ras activation and absence of p53 protein accumulation in aberrant crypt foci of the colon. Gastroenterology 108:434-440, 1995

    Google Scholar 

  13. Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vogelstein B, Kinzler KW: Molecular determinants of dysplasia in colorectal lesions. Cancer Res 54:5523-5526, 1994

    Google Scholar 

  14. Tudek B, Bird RP, Bruce WR: Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods. Cancer Res 49:1236-1240, 1989

    Google Scholar 

  15. Wargovich MJ, Chen C, Jimenez A, Steele VE, Velasco M, Stephens LC, Price R, Gray K, Kelloff GJ: Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat. Cancer Epidemiol Biomarkers Prev 5:355-360, 1996

    Google Scholar 

  16. Pretlow TP, Barrow BJ, Ashton WS, O'Riordan MA, Pretlow TG, Jurcisek JA, Stellato TA: Aberrant crypts: Putative preneoplastic foci in human colonic mucosa. Cancer Res 51:1564-1567, 1991

    Google Scholar 

  17. Roncucci L, Medline A, Bruce WR: Classification of aberrant crypt foci and microadenomas in human colon. Cancer Epidemiol Biomarkers Prev 1:57-60, 1991

    Google Scholar 

  18. Caderni G, Giannini A, Lancioni L, Luceri C, Biggeri A, Dolara P: Characterization of aberrant crypt foci in carcinogen-treated rats: Association with intestinal carcinogenesis. Br J Cancer 71:763-769, 1995

    Google Scholar 

  19. Carter JW, Lancaster HK, Hardman WE, Cameron IL: Distribution of intestine-associated-lymphoid-tissue, aberrant crypt foci and tumors in the large bowel of 1,2-dimethylhydrazine-treated mice. Cancer Res 54:4304-4307, 1994

    Google Scholar 

  20. Hardman WE, Cameron IL: Letter to the editor. Carcinogenesis 17:1539-1540, 1996

    Google Scholar 

  21. Wargovich MJ, Chen CD, Harris C, Yang E, Velasco M: Inhibition of aberrant crypt growth by non-steroidal antiinflammatory agents and differentiation agents in the rat colon. Int J Cancer 60:515-519, 1995

    Google Scholar 

  22. Lasko CM, Bird RP: Modulation of aberrant crypt foci by dietary fat and caloric restriction: The effects of delayed intervention. Cancer Epidemiol Biomarkers Prev 4:49-55, 1995

    Google Scholar 

  23. Lee M, Feldman M: Nonessential role of leukotrienes as mediators of acute gastric mucosal injury induced by aspirin in rats. Dig Dis Sci 37:1282-1287, 1992

    Google Scholar 

  24. Cameron IL, Ord VA, Hunter KE, Heitman DW: Colon carcinogenesis: Modulation of progression. In Colon Cancer Cells. MP Moyer, G Poste (eds). Orlando, Academic Press, 1990, pp 63-84

    Google Scholar 

  25. Bird RP: Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: Preliminary findings. Cancer Lett 37:147-151, 1987

    Google Scholar 

  26. SAS Institute: SAS Language and Procedures: usage. Cary, North Carolina, SAS Institute, 1989

    Google Scholar 

  27. Pence BC, Dunn DM, Zhao C, Landers M, Wargovich MJ: Chemopreventive effects of calcium but not aspirin supplementation in cholic acid-promoted carcinogenesis: Correlation with intermediate endpoints. Carcinogenesis 16:757-765, 1995

    Google Scholar 

  28. Pollard M, Luckert PH: Prolonged antitumor effect of indomethacin on autochthonous intestinal tumors in rats. J Natl Cancer Inst 70:1103-1105, 1983

    Google Scholar 

  29. Kargman S, Charleson S, Cartwright M, Frank J, Riendeau D, Mancini J, Evans J, O'Neill G: Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and human gastrointestinal tracts. Gastroenterology 111:445-454, 1996

    Google Scholar 

  30. Abramson S, Korchak H, Ludewig R, Edelson H, Haines K, Levin RI, Herman R, Rider L, Kimmel S, Weissman G: Modes of action of aspirin-like drugs. Proc Natl Acad Sci USA 82:7227-7231, 1985

    Google Scholar 

  31. Abramson SB, Weissman G: The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 32:1-9, 1989

    Google Scholar 

  32. Kopp E, Ghosh S: Inhibition of NF-kB by sodium salicylate and aspirin. Science 265:956-959, 1994

    Google Scholar 

  33. Giardiello FM: Sulindac and polyp regression. Cancer Metast Rev 13:279-283, 1994

    Google Scholar 

Download references

Authors
  1. Christopher J. Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Elaine Hardman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivan L. Cameron
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Makau Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barnes, C.J., Hardman, W.E., Cameron, I.L. et al. Aspirin, but Not Sodium Salicylate, Indomethacin, or Nabumetone, Reversibly Suppresses 1,2-Dimethylhydrazine-Induced Colonic Aberrant Crypt Foci in Rats. Dig Dis Sci 42, 920–926 (1997). https://doi.org/10.1023/A:1018812430512

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018812430512

Search

Navigation