MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID

维甲酸抑制肿瘤促进期的多步致癌作用。我们研究了维甲酸类化合物对肝细胞癌的化学预防作用，最近证实了非环类维甲酸对第二原发癌发生的临床作用(New Engl J Med，334：1561-1567；1996)。截至1998年8月，维甲酸预防第二原发肝细胞癌的效果更加明显(经LOG检验，P=0.002)。此外，维甲酸组和安慰剂组的中位随访期为62个月，存活率有显著差异(P=0.04)。在随机选取的患者变量中，比例风险分析显示，非环类维甲酸的应用是显著提高患者存活率的唯一独立因素。与安慰剂组(New Engl J Med，出版中)相比，非环类维甲酸组的死亡相对危险度估计为0.3(95%可信区间，0.1至0.8)。我们阐明了维甲酸作用的两种可能机制：分化诱导和细胞凋亡诱导。在体外实验中，去环维A酸类化合物诱导分化，分化后1~4周，肝癌细胞因凋亡而死亡。其机制是从维甲酸与维甲酸X受体结合的信号开始的(Mol Carcination10：151-158,1994，Mol Cell Endocrinol 121：179-190,1996，Biochem BiPhys Commun 225：946-951,1996)。尽管去环维A酸显著增强caspase-3的活性，但全反式维甲酸或9-顺式维甲酸不能增强caspase-3的活性。我们认为这些结果对于用维甲酸进行癌症化学预防和开发新的癌症化学预防药物非常重要。

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.