Chemoprevention of familial adenomatous polyposis development in the APC(min) mouse model by 1,4-phenylene bis (methylene)selenocyanate

Epidemiological and experimental studies have suggested that dietary supple mentation with selenium can inhibit the development of cancers at several o rgan sites. We have consistently shown that 1,4-phenylene bis(methylene) se lenocyanate (p-XSC) is a highly effective cancer chemopreventive agent agai nst the development of chemically induced cancers in several laboratory ani mal species. This is the first report describing the preventive effects of p-XSC in an animal model of familial adenomatous polyposis (FAP) containing a germline mutation of the APC gene, Six-week old male (heterozygous) C57B L/6J-APC(min) or wild-type mice were fed high fat diets containing 0, 10 or 20 p.p.m. p-XSC. After 80 days, the mice were killed and their intestines were excised and evaluated for polyps, Multiple samples were also harvested from normal appearing small intestine and colon for molecular analysis. Bo th the mucosa and polyps from the intestine and colon were assayed for beta -catenin, cyclooxygenase (COX)-2 expression and COX isoform activities. Adm inistration of p-XSC in the diet significantly decreased the rate of format ion of small intestinal tumors (P < 0.0001) and colon tumors (P < 0.002) in APC(min) mice. p-XSC produced a dose-dependent inhibition of tumors in bot h small intestine (P < 0.0001) and colon (P < 0.035), Mice fed 20 p.p.m. p- XSC had significantly lower levels of beta-catenin expression and COX-2 act ivity in polyps. These observations demonstrate for the first time that the synthetic organoselenium compound p-XSC possesses antitumor activity again st genetically predisposed neoplastic lesions, such as FAP, While the exact mechanism(s) for this antitumor activity of p-XSC remains to be elucidated , it appears that modulation of beta-catenin expression and COX-2 activity is associated with inhibition of intestinal polyps.