Enhancement of murine hepatocarcinogenesis by all-trans-retinoic acid and two synthetic retinamides

Although retinoids have significant chemopreventive activity in many in vivo carcinogenesis models, their influence on experimental hepatocarcinogenesis has received only limited study. The present experiment was designed to determine the effects of three retinoids on hepatocarcinogenesis induced in female B6D2F1 mice by diethylnitrosamine (DEN). Beginning 1 week after a single i.p. dose of 0, 50 or 100 mg DEN per kg body wt, groups of 35 mice received dietary supplements of (per kg diet): 0.1 mmol all-trans-retinoic acid (RA), 0.5 or 1.0 mmol all-trans-ethyl retinamide (ER), 0.5 or 1.0 mmol 13-cis-ethyl retinamide (13-cis-ER), or vehicle only. In mice treated with 100 mg DEN/kg, all three retinoids significantly increased the incidence of liver tumors (benign + malignant) from the level seen in dietary controls; significant increases in the incidence of hepatocellular carcinoma were seen in groups fed ER. At the lower DEN dose, all three retinoids significantly increased the incidence of total liver tumors and of hepatocellular carcinomas. In mice not treated with DEN, liver tumors were seen only in mice fed ER or 13-cis-ER at 1.0 mmol/kg diet. These data indicate that RA, ER and 13-cis-ER can promote liver carcinogenesis in mice when administered at doses that inhibit cancer induction in other tissues. Because chronic exposure to many retinoids results in the deposition and accumulation of both parent compound and metabolites in the liver, these results should suggest caution in the design of clinical chemoprevention trials with this class of compounds.