MODIFYING EFFECTS OF THE AROTINOID MOFAROTENE (RO-40-8757) ON AZOXYMETHANE-INDUCED RAT COLON AND LIVER CARCINOGENESIS

Background - As well as being efficient therapeutic agents, retinoids are considered to be the most promising among chemopreventive agents. However, relatively high doses and mostly long-term treatment are requ ired to achieve such effects. Arotinoids have been found to have consi derable anti-tumor activity in vivo and in vitro. The arotinoid mofaro tene (Ro 40-8757) is the most active arotinoid, but has not been teste d for ifs ability to prevent colon canter. Methods - In this study, th e modulating effect of dietary administration of Ro 40-8757 during the initiation and postinitiation phases of colon carcinogenesis initiate d with azoxymethane (AOM) were investigated in male F344 rats. Animals were initiated with AO by weekly s.c. injections of 20 mg/kg body wei ght for 3 weeks. They were fed the diets containing Ro 40-8757 at conc entrations of 100, 200, and 500 ppm during the initiation stage for 4 weeks, starting one week before the first dose of AOM or the postiniti ation stage for 33 weeks, starting one week after the last injection o f AOM. Other groups included rats treated with Ro 40-8757 alone (500 p pm) and untreated. The end-points used in this study were incidence an d multiplicity of tumors. Results - At the end of the study (weeks 37) , the incidence and multiplicity of intestinal neoplasms in the large intestine of rats given AOM together with or followed by Ro 40-8757 me re generally smaller than those of rats treated with AOM alone, withou t dose-response effects. Feeding of 200 ppm Ro 40-8757 during the init iation phase and 100 ppm Ro 40-8757 during the postinitiation phase si gnificantly lowered the incidence of intestinal adenocarcinoma and the frequency of large intestinal adenocarcinoma, respectively (p<0.05). Feeding of Ro 40-8757 at 500 ppm during initiation stage significantly reduced the multiplicity of intestinal adenocarcinoma (p<0.05). Also, dietary exposure of 100 ppm and 500 ppm Ro 40-8757 significantly lowe red the multiplicities of intestinal and/or colon adenocarcinoma (p<0. 05 and p<0.001). Ro 40-8757 feeding at higher doses during either the initiation or postinitiation phase significantly inhibited the develop ment of aberrant crypt foci induced by AOM, Ro 40-8757 feeding signifi cantly reduced the occurrence of Liver cell foci, which are precursor lesions of liver cell neoplasms. Dietary exposure of Ro 40-8757 also d ecreased cell proliferation activity, as revealed by measuring the 5'- bromodeoxyuridine-labeling index in crypt cells, colonic mucosal ornit hine decarboxylase activity, and blood polyamine levels, but no statis tical significance was observed. Conclusions - These results indicate that Ro 40-8757 may have weak chemopreventive effects on colon and liv er carcinogenesis, although it is not certain that these results can b e translated to human chemoprevention studies.