MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID

维甲酸抑制多步骤癌变的肿瘤促进阶段。我们已经进行了用类维生素A化学预防肝细胞癌的研究，最近证实了无环类维生素A对第二原发性肝癌发生的临床作用（New Engl J Med，334：1561-1567 ; 1996）。截至1998年8月，类维生素A在预防第二原发性肝细胞癌方面的作用更加明显（对数秩检验P=0.002）。此外，类维生素A组和安慰剂组之间的生存率存在显著差异，中位随访时间为62个月（P=0.04）。在随机化时选定的患者变量中，比例风险分析显示，给予非环类维生素A是显著改善患者生存率的唯一独立因素。与安慰剂组相比，无环类维生素A组估计的相对死亡风险为0.3（95%置信区间，0.1 ~ 0.8）（New Engl J Med，出版中）。我们阐明了类维生素A作用的两种可能机制：分化诱导和凋亡诱导。在体外研究中，无环类维生素A诱导分化，肝癌细胞随后在细胞分化后1至4周由于凋亡而死亡。该机制是由类视色素与类视色素X受体结合开始的信号发挥作用的（Mol Carcinogenesis 10：151-158，1994，Mol Cell Endocrinol 121：179-190，1996，Biochem Biophys Res Commun 225：946-951，1996）。虽然无环类维生素A显着增强caspase-3的活性，全反式维甲酸或9-顺式维甲酸没有增强它。我们评估这些结果是非常重要的，以建立与类维生素A的癌症化学预防和开发新的癌症化学预防剂。

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.