MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID

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Retinoid inhibit the tumor promotion phase of mutistep carcinogenesis. We have conducted investigations of chemoprevention of hepatocellular carcinoma by retionoids and recently confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis (New Engl J Med, 334 : 1561-1567 ; 1996). As of August 1998 the effect of the retinoid in preventing second primary hepatocellular carcinomas was even more evident (P=0.002 by the log-rank test). Moreover, a significant difference in the survival rate between the retinoid and the placebo groups with a median follow-up of 62 months (P=0.04). Among selected patients variables at the time of randomization, proportional hazards analysis revealed that the administration of acyclic retinoid was the only independent factor that significantly improved survival of the patients. The estimated relative risk of death was 0.3 (95 percent confidence interval, 0.1 to 0.8) in the acyclic retinoid group as compared with the placebo group (New Engl J Med, in press).We have elucidated two possible mechanisms of retinoid action ; differentiation induction and apoptosis induction. In vitro study, acyclic retinoid induced differentiation and the hepatoma cells subsequently died due to apoptosis 1 to 4 weeks after cellular differentiation. The mechanism was exerted by a signal which started with the binding of retinoid with retinoid X receptor (Mol Carcinogenesis 10 : 151-158, 1994, Mol Cell Endocrinol 121 : 179-190, 1996, Biochem Biophys Res Commun 225 : 946-951, 1996). Although acyclic retinoid significantly enhanced caspase-3 activity, all-trans retinoic acid or 9-cis retinoic acid did not enhance it.We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.