title: Non-steroidal anti-inflammatory drugs with different cyclooxygenase inhibitory profiles that prevent aberrant crypt foci formation but vary in acute gastrotoxicity in a rat model.
abstract: BACKGROUND
  Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer; however, their use as preventive agents is limited by their inherent toxicity. Drugs that selectively inhibit cyclooxygenase-2 (COX-2) may be useful in this setting as they are supposedly less toxic. No study has directly compared the ability of standard NSAIDs and selective COX-2 inhibitors to inhibit colorectal cancer at clinically relevant doses.
  
  
  METHODS
  Aberrant crypt foci (ACF) were induced in Sprague-Dawley rats by using 1,2-dimethylhydrazine (DMH). Test agents or vehicle were then administered for 3 weeks, twice daily through orogastric gavage. At the end of this period, the number and multiplicity of ACF were determined. The agents tested at equivalent anti-inflammatory doses were: sulindac and indomethacin (standard NSAIDs), meloxicam (selective COX-2 inhibitor), celecoxib (specific COX-2 inhibitor) and sulindac sulfone (no known COX activity). Acute gastrotoxicity of NSAID in rats was compared by using quantitative histology.
  
  
  RESULTS
  All test agents reduced the number of ACF. There was a 42% reduction with indomethacin, 46% with sulindac, 46% with meloxicam, 22% with celecoxib and 36% with sulindac sulfone. Only the COX-2 inhibitors caused no significant gastrotoxicity in rats.
  
  
  CONCLUSIONS
  Cyclooxygenase-2 inhibitors are potentially ideal chemopreventive agents as they inhibit ACF and are not gastrotoxic.
authors.affiliation: Monash University Department of Surgery, Alfred Hospital, Commercial Road, Prahran, Victoria 3181, Australia. wendy.brown@med.monash.edu.au
authors.forename: W A
authors.initials: WA
authors.lastname: Brown
authors.forename: S A
authors.initials: SA
authors.lastname: Skinner
authors.forename: C
authors.initials: C
authors.lastname: Malcontenti-Wilson
authors.forename: A
authors.initials: A
authors.lastname: Misajon
authors.forename: T
authors.initials: T
authors.lastname: DeJong
authors.forename: D
authors.initials: D
authors.lastname: Vogiagis
authors.forename: P E
authors.initials: PE
authors.lastname: O'Brien
mesh_terms: D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D011230:Precancerous Conditions / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects* / Q000473:pathology*; D013272:Stomach Diseases / Q000139:chemically induced*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors