SULINDAC AND INDOMETHACIN INHIBIT FORMATION OF ABERRANT CRYPT FOCI INTHE COLONS OF DIMETHYL HYDRAZINE TREATED RATS

Aberrant crypt foci are microscopic lesions found in the colons of rod ents treated with carcinogens, and in patients with premalignant color ectal conditions. They consist of single or multiple abnormal crypts a nd show cellular changes ranging from dysplasia to microscopic adenoma carcinoma. It is thought that these lesions represent the initial stag es of the adenomacarcinoma path that results in the development of col orectal neoplasia. We have examined the effect of sulindac and indomet hacin on the formation of aberrant crypt foci in rats treated with dim ethylhydrazine (DMH). Aberrant crypt foci were induced in male Sprague -Dawley rats with two oral doses of dimethyl hydrazine at 25 mg/kg per dose. Rats were randomized to receive sulindac at 3 mg/kg (n=20) or 1 0 mg/kg (n=18) b.d., indomethacin at 1 mg/kg per day (n=18) or 2 mg/kg per day (n=19) or control (n=37). Drug treatment was starred on the d ay following the first dose of carcinogen and continued for 3 weeks. C olons were fixed flat overnight in 10% formalin and stained with 0.2% Methylene Blue solution before being studied. There was a significant reduction in the number of aberrant crypt foci in rats treated with 10 mg/kg b.d. sulindac (P=0.001) and indomethacin at 2 mg/kg per day (P= 0.0002). Sulindac, at 3 mg/kg b.d., and indomethacin, at 1 mg/kg per d ay, did not have a statistically significant effect (P=0.089 and P=0.0 52, respectively). None of the drug treatments affected the relative f requency of single crypt vs multiple crypt foci. Previous studies have shown that sulindac and indomethacin will significantly inhibit the g rowth and development of tumours in DMH treated rats. The current data suggest that one of the pathways of action of NSAID is to inhibit the formation of early preneoplastic lesions.