MODIFYING EFFECTS OF NATURALLY-OCCURRING PRODUCTS ON THE DEVELOPMENT OF COLONIC ABERRANT CRYPT FOCI INDUCED BY AZOXYMETHANE IN F344 RATS

Modifying effects of dietary exposure of seven naturally occurring pro ducts on the development of colonic aberrant crypt foci (ACF) induced by azoxymethane (AOM) were investigated in male F344 rats. The effects of these compounds on proliferation biomarkers such as the number of silver-stained nucleolar organizer region protein, ornithine decarbo?i Silase activity, and polyamine concentration in the colon were also es timated. The naturally occurring products tested included four terpeno ids (rebaudioside A, oleanolic acid, costunolide, and soyasaponin A(2) ), one flavonoid (liquiritin), and two isocoumarins (phyllodulcin and hydrangenol). Animals were given 3 weekly s.c. injections of AOM (15 m g/kg body weight) to induce ACF. These rats were fed the diet containi ng 200 ppm of each test chemical for 5 weeks, starting 1 week before t he first dosing of AOM. All rats were sacrificed 2 weeks after the las t AOM injection to estimate their modulatory effects on the occurrence of ACF and the cell proliferation biomarkers in the colon. In groups of rats given AOM and hydrangenol, oleanolic acid, or costunolide, the frequencies of ACF/colon were significantly lower than that of AOM al one (P < 0.05, P < 0.005, and P < 0.05, respectively). In groups of Fa ts given AOM and costunolide and those treated with AOM and soyasaponi n A(2), both ornithine decarboxylase activity and polyamine concentrat ion of the colonic mucosal tissue mere significantly decreased compare d with those in rats given AOM alone (P < 0.05 and P < 0.001 for costu nolide and P < 0.001 and P < 0.05 for soyasaponin A(2), respectively). In groups of rats given AOM and liquiritin, oleanolic acid, or costun olide, the numbers of silver-stained nucleolar organizer regions/nucle us were significantly lower than that of AOM alone (P < 0.05, P < 0.01 , and P < 0.05, respectively). Costunolide decreased four AOM-induced biomarkers, such as the frequencies of ACF/colon, ornithine decarboxyl ase activity, polyamine concentration level, and silver-stained nucleo lar organizer region number in the colon. These results indicate that, among the test chemicals, costunolide has blocking effects against ra t colon carcinogenesis and is a possible chemopreventive agent against colon tumorigenesis. Also, the short-term model described here could be a very useful prescreening tool for chemopreventive agents against colon cancer.