Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase?

David S Alberts, L. Hixson, D. Ahnen, C. Bogert, Janine G Einspahr, N. Paranka, K. Brendel, P. H. Gross, R. Pamukcu, R. W. Burt

Research output: Contribution to journalArticle

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Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potential as chemopreventive agents for colorectal cancer. Recent case-control drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/or decreased death rate from this disease. Several different NSAIDs reduce formation of both colon adenomatous polyps (the precursor lesion of colon cancer) and cancers in experimental animals given known carcinogens. Perhaps most convincing are reports that the NSAID sulindac promotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized pharmacologic effect of the NSAIDs is their reduction of prostaglandin synthesis by inhibiting prostaglandin synthetase PGE2, which catalyzes the formation of prostaglandin precursors from arachidonic acid. Several lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effects. Relatively high levels of prostaglandins have been reported to inhibit tumor cell growth both in vivo and in vitro, and to inhibit differentiation in some tumor cell lines. We evaluated comparative chemopreventive effects on colon tumor formation in an azoxymethane (AOM)- induced colon carcinogenesis rat model using the NSAIDs piroxicam, sulindac, and sulindac sulfone, a metabolite of sulindac which lacks the anti- prostaglandin synthetase activity typically associated with NSAID-induced gastrointestinal toxicities. The results demonstrate that sulindac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM- induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone- treated animals. Although both piroxicam and sulindac significantly reduced rat colonic mucosal PGE2 levels to less than 50% of their AOM control value, even the highest dietary concentration of sulindac sulfone had no statistically significant effect on mucosal PGE2 concentrations. These results suggest that NSAIDs do not exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase.

Original languageEnglish (US)
Pages (from-to)18-23
Number of pages6
JournalJournal of Cellular Biochemistry
Volume58
Issue numberSUPPL. 22
StatePublished - 1995

Fingerprint

Chemoprevention
Prostaglandin-Endoperoxide Synthases
Colonic Neoplasms
Anti-Inflammatory Agents
Sulindac
Azoxymethane
Tumors
Pharmaceutical Preparations
Prostaglandins
Colon
Dinoprostone
Adenomatous Polyps
Piroxicam
Rats
Colorectal Neoplasms
Neoplasms
Animals
Gastrointestinal Agents
Adenomatous Polyposis Coli
Drug and Narcotic Control

Keywords

  • Colon cancer prevention
  • NSAIDs
  • sulindac
  • sulindac sulfone

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase? / Alberts, David S; Hixson, L.; Ahnen, D.; Bogert, C.; Einspahr, Janine G; Paranka, N.; Brendel, K.; Gross, P. H.; Pamukcu, R.; Burt, R. W.

In: Journal of Cellular Biochemistry, Vol. 58, No. SUPPL. 22, 1995, p. 18-23.

Research output: Contribution to journalArticle

Alberts, DS, Hixson, L, Ahnen, D, Bogert, C, Einspahr, JG, Paranka, N, Brendel, K, Gross, PH, Pamukcu, R & Burt, RW 1995, 'Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase?', Journal of Cellular Biochemistry, vol. 58, no. SUPPL. 22, pp. 18-23.
Alberts, David S ; Hixson, L. ; Ahnen, D. ; Bogert, C. ; Einspahr, Janine G ; Paranka, N. ; Brendel, K. ; Gross, P. H. ; Pamukcu, R. ; Burt, R. W. / Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase?. In: Journal of Cellular Biochemistry. 1995 ; Vol. 58, No. SUPPL. 22. pp. 18-23.
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AU - Einspahr, Janine G

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