MECHANISMS OF CLONAL DELETION OF HEPATOCELLULAR CARCINOMA BY ACYCLICRETINOID

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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 confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis (New Engl J Med, 1996). Moreover, we reveled 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, 340 : 1046-1047 ; 1999).Acyclic retinoid prevents hepatocarcinogenesis by eradicating premalignant and latent malignant clones of transformed cells from the liver. We demonstrate the mechanism of this clonal deletion at the cellular level. Production of albumin was recovered while that of AFP-L3 was reduced after exposure of the cells to acyclic retinoid for 2 days. In parallel, both TERT mRNA expression and telomerase activity were down-regulated. The cells subsequently died due to apoptosis. Serial increases in mitochondrial membrane permeability and caspase-9 and -3 activities induced apoptosis. Acyclic retinoid first induces differentiation and reduces telomerase activity. Subsequent late apoptosis completes the clonal deletion of the cells.We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.