kyn-54 and Colonic-Neoplasms

Regressive effects of four chemopreventive agents [5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone (KYN-54), S-methyl methanethiosulfonate (MMTS), chlorogenic acid (CA), and piroxicam] on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in the colon of male F344 rats were examined by dietary exposure. At six weeks of age, 60 rats of groups 1 through 5 received subcutaneous injections of AOM (15 mg/kg body weight) once a weeks. Twelve weeks after the first carcinogen injection, when the occurrence of ACF was maximal, the rats in groups 2 through 5 were started on diet containing the test chemicals as follows: group 2, KYN-54 (0.02%); group 3, MMTS (0.01%); group 4, CA (0.025%); and group 5, piroxicam (0.0125%). Group 1 (20 rats) was kept on the basal diet alone, and group 6 (12 rats) served as an untreated control. Rats in each group were killed at 6, 12, 18, or 24 weeks after the start of the experiment, and the yield of ACF in the colon of each group at 18 or 24 weeks was compared with that at 12 weeks. The number of ACF per rat colon of each group at 18 or 24 weeks was smaller than that at 12 weeks. The reduction rates at 18 weeks were 7% in group 1 (AOM alone), 11% in group 2 (AOM + KYN-54), 10% in group 3 (AOM + MMTS), 51% in group 4 (AOM + CA) (P < 0.01), and 33% in group 5 (AOM + piroxicam) (P < 0.02), while at 24 weeks they were 12%, 26%, 51% (P < 0.002), 43% (P < 0.05), and 70% (P < 0.001), respectively. These results indicate that chemopreventive agents for large bowel carcinogenesis, i.e., KYN-54, MMTS, CA, and piroxicam, are not only able to prevent the development of ACF, but also can regress ACF, which are regarded as precursor lesions of colorectal cancer.

Topics: 4-Butyrolactone; Animals; Anticarcinogenic Agents; Azoxymethane; Body Weight; Carcinogens; Chemoprevention; Chlorogenic Acid; Colonic Neoplasms; Drug Administration Schedule; Male; Methyl Methanesulfonate; Piroxicam; Rats; Rats, Inbred F344; Retinoids

The modifying effect of dietary exposure to a novel synthesized retinoidal butenolide, 5-hydroxy-4-(2-phenyl-(E)ethenyl)-2(5H)-furanone (KYN-5) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in male F344 rats. Animals were given weekly s.c. injections of AOM (15 mg/kg body wt.) for 3 weeks to induce ACF. These rats were fed diet containing 100 or 200 ppm KYN-54 for 5 weeks, starting 1 week before the first dosing of AOM. All rats were killed 2 weeks after the last AOM injection, to measure the number of ACF, ornithine decarboxylase (ODC) activity, mucosal polyamine level, and silver-stained nucleolar organizer regions protein (AgNORs) count per nucleus in the colon. In rats given AOM and KYN-54, the frequency of ACF/colon was significantly decreased compared with that in rats given AOM alone. ODC activity and polyamine levels, and the mean AgNORs number in the colon of rats given AOM and KYN-54 at both doses were also significantly lower than that of rats treated with AOM alone. These results provide further evidence that KYN-54 could be a chemopreventive agent against rat colon carcinogenesis.

Topics: 4-Butyrolactone; Animals; Anticarcinogenic Agents; Azoxymethane; Biogenic Polyamines; Biomarkers, Tumor; Body Weight; Cell Division; Colonic Neoplasms; Epithelium; Intestinal Mucosa; Liver; Male; Nucleolus Organizer Region; Organ Size; Ornithine Decarboxylase; Rats; Rats, Inbred F344; Retinoids; Silver Staining