Sulindac and indomethacin inhibit formation of aberrant crypt foci in the colons of dimethyl hydrazine treated rats

Abstract

Aberrant crypt foci are microscopic lesions found in the colons of rodents treated with carcinogens, and in patients with premalignant colorectal conditions. They consist of single or multiple abnormal crypts and show cellular changes ranging from dysplasia to microscopic adenomacarcinoma. It is thought that these lesions represent the initial stages of the adenomacarcinoma path that results in the development of colorectal neoplasia. We have examined the effect of sulindac and indomethacin on the formation of aberrant crypt foci in rats treated with dimethylhydrazine (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 10 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 started on the day following the first dose of carcinogen and continued for 3 weeks. Colons 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 day, did not have a statistically significant effect (P = 0.089 and P = 0.052, respectively). None of the drug treatments affected the relative frequency of single crypt vs multiple crypt foci. Previous studies have shown that sulindac and indomethacin will significantly inhibit the growth 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.

Short term infusion of glycine-extended gastrin17 stimulates both proliferation and formation of aberrant crypt foci in rat colonic mucosa

“…34 A number of reports studying the potential chemopreventative effect of non-steroidal anti-inflammatory agents have described a reduction in aberrant crypt foci and subsequent tumour formation. 35,36 Our study clearly demonstrates that glycine-extended gastrin 17 increases the number of aberrant crypt foci formed in the colorectal mucosa of rats after treatment with azoxymethane in a pattern consistent with its action as a proliferative agent in the colonic mucosa. Glycine-extended gastrin 17 could thus potentially act as a promoter of carcinogenesis, but definitive evidence for this proposal would require a long term study to establish that tumors occur either earlier, or more abundantly, or both, in rats treated with glycine-extended gastrin 17 compared to controls.…”

“…Previous work on the ACF model suggests that in general increases in ACF number are associated with a subsequent increase in tumour frequency. 32,35,36 In the case of transgenic mice overexpressing progastrin the increase in number of aberrant crypt foci after treatment with azoxymethane compared to wildtype controls 9 is ultimately followed by the development of greater numbers of larger adenomas and adenocarcinomas of the colon. 30 The implications of these findings for human disease are still to be elucidated.…”

Celecoxib Treatment Alters the Gene Expression Profile of Normal Colonic Mucosa

“…ACFs are considered to be an early preneoplastic lesion in the colon (75), and the ability to decrease the frequency of ACF after carcinogen treatment is used routinely in experimental models of colon cancer to estimate the cancer preventive effect of different agents (76). It is particularly well established that NSAIDs (77)(78)(79) and celecoxib (80)(81)(82)(83) decrease the frequency of carcinogen-induced ACFs in the colon in animal models. It has also been shown that the number of ACF in patients who received sulindac sulfide is decreased (84).…”

Dietary Putrescine Reduces the Intestinal Anticarcinogenic Activity of Sulindac in a Murine Model of Familial Adenomatous Polyposis

“…Reduction of COX enzyme activity by NSAIDs suppresses intestinal carcinogenesis in Apc Min/+ mice (24)(25)(26) as well as other models of intestinal cancer (7,(27)(28)(29)(30). Expression of polyamine biosynthetic enzyme, ornithine decarboxylase (ODC), is elevated in the intestinal tissues of Apc Min/+ mice and in apparently normal colonicmucosal biopsies from FAP patients (31,32).…”