MECHANISMS OF CLONAL DELETION OF HEPATOCELLULAR CARCINOMA BY ACYCLICRETINOID

类维生素a抑制多步癌变的肿瘤促进期。我们开展了类retionid对肝细胞癌的化学预防研究，证实了无环类retionid对第二原发性肝癌发生的临床疗效（New Engl J Med, 1996）。此外，我们发现类维生素a组和安慰剂组的生存率有显著差异，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，给予无环类维甲酸是唯一显著改善患者生存的独立因素。与安慰剂组相比，无环类维甲酸组的估计相对死亡风险为0.3(95%可信区间，0.1至0.8)（New Engl J Med, 340: 1046-1047; 1999）。无环类维甲酸通过根除肝脏转化细胞的癌前和潜伏恶性克隆来防止肝癌的发生。我们在细胞水平上证明了这种克隆缺失的机制。细胞暴露于无环类维甲酸2天后，白蛋白的产生恢复，而AFP-L3的产生减少。同时，TERT mRNA表达和端粒酶活性均下调。细胞随后因凋亡而死亡。线粒体膜通透性和caspase-9和-3活性的连续增加诱导细胞凋亡。无环类维甲酸首先诱导分化并降低端粒酶活性。随后的晚期凋亡完成了细胞的克隆缺失。我们认为这些结果对建立化学预防癌症和开发新的癌症化学预防药物具有重要意义。

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.