MECHANISMS OF CLONAL DELETION OF HEPATOCELLULAR CARCINOMA BY ACYCLICRETINOID

环状维A酸克隆删除肝细胞癌的机制

基本信息

批准号：
10557055
负责人：
MORIWAKI Hisataka
金额：
$ 3.78万
依托单位：
GIFU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

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.

类视网膜类似抑制Mutistep癌变的肿瘤促进阶段。我们已经通过肉变素对肝细胞癌的化学预防进行了研究，并证实了无环性尿素对第二次原发性肝癌发生的临床作用（New Engl J Med，1996）。此外，我们在类维生素类似物和安慰剂组之间的存活率显着差异，中位随访时间为62个月（p = 0.04）。在随机分组时选定的患者变量中，比例危害分析表明，无环性类维生素类动物的给药是唯一显着提高患者存活率的独立因素。 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.我们证明了这种克隆缺失在细胞水平上的机制。回收白蛋白的产生，而在细胞暴露于无环性类维生素激素后，AFP-L3的产生降低了2天。同时，TERT mRNA表达和端粒酶活性都被下调。细胞随后由于凋亡而死亡。线粒体膜通透性以及caspase -9和-3活性诱导细胞凋亡的序列增加。无环类视网膜类似首先诱导分化并降低端粒酶活性。随后的晚期细胞凋亡完成了细胞的克隆缺失。我们评估这些结果对于建立癌症的化学预防非常重要，并开发了新型的癌症化学预防剂。