Sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene] indene-3-acetic acid), an inhibitor of prostaglandin synthesis, has been reported to cause regression of colon polyps in patients with familial polyposis coli and Gardner's syndrome. We examined the effect of sulindac on the growth of primary colon carcinomas in rats. Colon tumors were induced in 18 rats by repeated subcutaneous administration of dimethylhydrazine. The site and diameter of each tumor were measured via laparotomy and colonoscopy. Rats were randomized to receive either sulindac (10 mg/kg) twice daily or vehicle (0.5% methylcellulose). After 4 weeks of treatment, the site and size of tumors in the colon were again recorded. In eight rats receiving sulindac, no new tumors were identified, while in 10 control rats, 13 additional tumors were found after treatment. There was a significantly greater increase in size of the tumors in the control group (56.4 mm for 26 tumors) compared with the rats receiving sulindac (9.3 mm for 14 tumors). We report that sulindac inhibits the rate of development and the rate of growth of colon tumors in the rat.

Clinical studies have suggested that treatment with the prostaglandin E1 analog, misoprostol, leads to significant healing of ulcers in patients taking regular nonsteroidal antiinflammatory therapy. This study aimed to investigate mechanisms involved in this healing using a rat model. Gastric ulcers were induced by application of acetic acid using a standard technique. Rats were treated with 200 mg/kg aspirin, 100 micrograms/kg misoprostol, a combination of both treatments, or methylcellulose vehicle for up to two weeks, starting two days after ulcer induction. Ulcers were assessed by macroscopic measurements of area and by quantitative histological measurements. Aspirin delayed ulcer healing compared with controls, while misoprostol significantly reversed this effect. Quantitative histology revealed that misoprostol cotreatment significantly increased mucosal regeneration compared with aspirin treatment alone. However, misoprostol did not reverse the effects of aspirin on an index of wound contraction. We conclude that treatment with misoprostol significantly reverses the delayed healing effect of aspirin, and this may occur via an effect on epithelial regeneration.

Nonsteriodal antiinflammatory drugs initiate gastric ulceration and delay gastric ulcer healing. This study aimed to investigate the role of epithelial cell proliferation in delayed ulcer healing and to identify the most reproducible technique for measuring cell proliferation. Rats with acetic acid-induced gastric ulcers were treated for two weeks with indomethacin (1 mg/kg), aspirin (200 mg/kg), or vehicle control. Ulcers were assessed by macroscopic measurement of ulcer area, quantitative histological measurement of mucosal regeneration, and 5-bromo-2'-deoxyuridine immunohistochemistry to assess epithelial cell proliferation. Indomethacin and aspirin significantly delayed ulcer healing and inhibited mucosal regeneration. Three techniques for assessing cell proliferation were compared, and a scoring system, designed to take into account the entire tissue, was shown to be the most reproducible technique. Indomethacin significantly enhanced cell proliferation in the fundic area of ulcer and aspirin had no effect on cell proliferation. We conclude that aspirin and indomethacin delay ulcer healing by an inhibition of mucosal regeneration, but they do not inhibit epithelial cell proliferation.

This study aimed to investigate the effect of age on natural ulcer healing and delayed ulcer healing induced by nonsteroidal antiinflammatory drugs, using a rat model. Gastric ulcers were induced in young, adult, and aged rats using serosal or mucosal (kissing ulcers) application of acetic acid. Rats were treated with indomethacin 1 mg/kg/day subcutaneously or vehicle for two weeks. Ulcers were assessed by macroscopic and histological measurements of ulcer size. Ulcer induction was affected by age. Aged rats developed significantly smaller ulcers when induced by serosal application of acetic acid and significantly larger ulcers from mucosal application of acetic acid. However, measurements of ulcer size from both models showed no age-related differences in natural ulcer healing. Similarly, indomethacin-induced delayed gastric ulcer healing was not effected by age. We conclude that there are age-related differences in the development of gastric ulcers but there are no age-related differences in natural or delayed ulcer healing in rats.

Prostaglandin E2 (PGE2), colloidal bismuth subcitrate (CBS), and sucralfate (SUC) are known to protect the gastric mucosa from ethanol injury. The proposed central role for the microcirculation in gastric mucosal defense and as a site for the expression of the protective effects of these agents was investigated in the rat stomach. Animals were pretreated with either PGE2, CBS, or SUC. Control rats were given normal saline. After allowing 15 min for expression of the pretreatment, ethanol was administered as a 10%, 25%, 50%, or 100% solution to groups of rats with normally perfused stomach and to other groups of rats in whom the stomach was made ischemic by cross-clamping the supracoeliac aorta immediately prior to the instillation of ethanol. The extent of gastric mucosal damage was measured using quantitative histological techniques and expressed as a percentage of surface area and volume of mucosa damaged. In the presence of ischemia, the extent of damage by ethanol was markedly increased, with total destruction of the mucosa by the 50% and 100% solutions. With 25% ethanol, the volume of mucosal damage was increased from 0.5% in the normally perfused stomach to 53.5% with ischemia. When 10% ethanol was instilled into the ischemic stomach, only 0.8% of the volume of the mucosa was damaged, which was not different from the volume of mucosa damaged after the ischemic stomach was exposed to normal saline alone (1.0%). Pretreatment with PGE2, CBS, or SUC did not significantly change the extent of damage seen with exposure of the ischemic stomach to 25% or 50% ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)