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Effect of difluoromethylornithine (DFMO) on NSAID-induced intestinal injury in rats
1Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach, California 90822.
Abstract:
Combination therapy with difluoromethylornithine (DFMO) and a nonsteroidal antiinflammatory drug (NSAID) has been proposed for the chemoprevention of colonic neoplasia. The purpose of this study was to examine whether DFMO would affect NSAID-mediated intestinal injury. Male Sprague-Dawley rats were gavaged with 20 mg/kg of indomethacin, after seven days of exposure to drinking water with or without 2% DFMO. The rats were killed 24 or 48 hr later, and the small intestine removed for macroscopic and microscopic quantitation of intestinal injury by computerized image analysis. Seven days of DFMO alone had no effect on overall mucosal thickness, but did increase the depth of proximal intestinal crypts. Forty-eight hours after indomethacin, DFMO treatment decreased the number of indomethacin-induced ulcers and percent of the surface area ulcerated. However, DFMO also decreased the mucosal thickness, villus height, and crypt depth in indomethacin-treated rats. Thus although DFMO decreases macroscopic intestinal ulceration by indomethacin, the reduction in villus and crypt height suggests that it also impairs the mucosa's ability to recover from microscopic indomethacin-induced damage. This study shows DFMO does impact NSAID-mediated intestinal injury and therefore human trials with combinations of DFMO and NSAIDs should include monitoring for small intestinal injury.
Insights
Difluoromethylornithine (DFMO) reduces NSAID-induced ulcers but may impair intestinal healing. Further research is needed to understand DFMO
Area of Science:
- Pharmacology
- Gastroenterology
- Oncology
Background:
- Combination therapy with difluoromethylornithine (DFMO) and nonsteroidal anti-inflammatory drugs (NSAIDs) is explored for colonic neoplasia chemoprevention.
- NSAIDs can cause significant intestinal injury, necessitating an understanding of potential interactions with chemopreventive agents.
Purpose of the Study:
- To investigate the impact of DFMO on NSAID-mediated intestinal injury in a rat model.
- To assess whether DFMO influences the development or severity of indomethacin-induced gastrointestinal damage.
Main Methods:
- Male Sprague-Dawley rats were administered indomethacin (20 mg/kg) after a seven-day exposure to drinking water containing either 2% DFMO or no DFMO.
- Intestinal injury was quantified macroscopically and microscopically using computerized image analysis 24 and 48 hours post-indomethacin administration.
Main Results:
- DFMO alone did not affect overall mucosal thickness but increased proximal intestinal crypt depth.
- DFMO treatment significantly decreased the number and surface area of indomethacin-induced ulcers at 48 hours.
- However, DFMO also reduced mucosal thickness, villus height, and crypt depth in indomethacin-treated rats, indicating impaired mucosal recovery.
Conclusions:
- While DFMO reduces macroscopic NSAID-induced intestinal ulceration, it also impairs microscopic mucosal recovery.
- These findings suggest that DFMO impacts NSAID-mediated intestinal injury.
- Human trials combining DFMO and NSAIDs should incorporate monitoring for small intestinal injury.
