Inhibition of aberrant crypt growth by non‐steroidal anti‐inflammatory agents and differentiation agents in the rat colon

Abstract

Aberrant crypts are aggregates of single to multiple colonic crypts evidencing hallmarks of dysplasia and may be the earliest detectable pathological lesions for colon cancer. The aberrant crypt assay has been developed in 2 protocols. In one, putative chemoprevention agents are tested for inhibitory effects when administered concomitantly with a carcinogen. In the other, the objective of this study, aberrant crypts were induced in F344 rats by parenteral injection of the colon carcinogen azoxymethane (AOM) and allowed to develop for 4 weeks, when an average of 90-100 aberrant crypt foci per colon were found in the methylene blue-stained colon. Then, during the second 4 weeks of the experiment, aberrant crypts were allowed to further develop to a frequency of > 150 foci per colon, a time when multi-crypt foci were observed. During this time we tested the inhibitory effects of 4 analgesic drugs and 2 differentiation agents for effects of aberrant crypt growth and development. We found the non-steroidal anti-inflammatory drugs piroxicam, aspirin and ibuprofen, but not acetaminophen, to be effective in suppressing aberrant crypt formation or the progression to foci of multiple aberrant crypts. Treatment with chemosuppressing agents 13-cis-retinoic acid (13-cRA) and 4-hydroxyphenretinamide (4-HPR), known differentiating agents, however, did suppress expansion of aberrant crypt foci, with 13-cRA being the much more potent agent.

Effect of Lactobacillus acidophilus KFRI342 on the development of chemically induced precancerous growths in the rat colon

“…Development of colon cancer is a multistep process involving a series of pathological alterations ranging from discrete microscopic mucosal lesions and ACF to malignant tumours (Takayama et al, 1998). ACF are induced specifically by carcinogens that predominantly elicit colonic tumours, and are considered to be precursors of colon cancer (Wargovich et al, 1995). Multiplicity of ACF increases with time and appears to be a predictor of tumour outcome.…”

“…Multiplicity of ACF increases with time and appears to be a predictor of tumour outcome. Thus, the DMH-induced colon cancer model in rats is a good tool to investigate the relationship between ACF and colon cancer, and also to evaluate agents with potential chemopreventive properties prior to preclinical studies (Wargovich et al, 1995). This efficient animal-tumour model was a useful approach to study Lactobacillus acidophilus KFRI342 during the initiation and post-initiation period, and to understand colon carcinogenesis.…”

Aberrant crypt foci: endoscopic assessment and cell kinetics characterization

“…The assumption that ACF are biomarkers of CRC has resulted from animal studies, which show that colon carcinogens induce the appearance of ACF [14] in a dose-related number [15]. The modulation of ACF by chemopreventive agents with proven activity in CRC is also described in animal studies [16][17][18]. With the emergence of magnification and chromoscopy, it is now possible to perform endoscopic in vivo human studies [19][20][21][22][23][24][25][26].…”

Chemoprevention of gastrointestinal malignancies with nonsteroidal antiinflammatory drugs

“…Aberrant crypts, which can be induced by chemical carcinogens, are believed to be the earliest detectable pathologic lesions in the development of colon carcinoma development. 64 Both piroxicam and aspirin have been shown to decrease the development of aberrant crypt foci. 64 Studies in Min mice have shown that aspirin can prevent the development of spontaneous intestinal adenomas.…”

“…64 Both piroxicam and aspirin have been shown to decrease the development of aberrant crypt foci. 64 Studies in Min mice have shown that aspirin can prevent the development of spontaneous intestinal adenomas. 65 High-dose aspirin was found to reduce tumor multiplicity and size significantly.…”