MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID

无环维A酸调控肝癌发生的机制

基本信息

  • 批准号:
    08670576
  • 负责人:
  • 金额:
    $ 1.6万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    1996
  • 资助国家:
    日本
  • 起止时间:
    1996 至 1998
  • 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 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.
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。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Matsushima-Nishiwaki R: "Aberabt metabolism of retinoid X receptor proteins in human hepatocellular carcinoma" Mol Cell Endocrinol. 121. 179-190 (1996)
Matsushima-Nishiwaki R:“人肝细胞癌中视黄醇 X 受体蛋白的 Aberabt 代谢”Mol Cell Endocrinol。
  • DOI:
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    0
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  • 通讯作者:
Muto Y.: "Prevention of second primary tumors by an acyclic retinoid,polyprenoic acid,in patients with hepatocellular carcinoma." Digestion. 59. 89-91 (1998)
Muto Y.:“通过无环类维生素A、聚戊烯酸预防肝细胞癌患者的第二原发肿瘤。”
  • DOI:
  • 发表时间:
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  • 影响因子:
    0
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Okuno M: "Retinoids exacerbate rat liver fibrosis by inducing the activation of laten TGF-β in liver stellate cells." Hepatology. 26. 911-921 (1997)
Okuno M:“类视黄醇通过诱导肝星状细胞中潜在的 TGF-β 的激活而加剧大鼠肝纤维化。” 26. 911-921 (1997)
  • DOI:
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    0
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  • 通讯作者:
Muto Y,Moriwaki H,Saito A.et al.: "Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma" N Engl J Med. (in press). (1999)
Muto Y、Moriwaki H、Saito A.et al.:“通过非环状维A酸预防肝细胞癌患者的第二原发肿瘤”N Engl J Med。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Okuno M.: "Protease inhibitors suppress TGF-β generation by hepatic stelate cells." J.Hepatol.29. 1031-1032 (1998)
Okuno M.:“蛋白酶抑制剂抑制肝星状细胞生成 TGF-β。”J.Hepatol.29(1998)。
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MORIWAKI Hisataka其他文献

MORIWAKI Hisataka的其他文献

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{{ truncateString('MORIWAKI Hisataka', 18)}}的其他基金

Combination chemoprevention of hepatocellular carcinoma with acyclic retinoid by targeting RXRαphosphorylation
靶向 RXRα 磷酸化的无环维A酸联合化学预防肝细胞癌
  • 批准号:
    21590838
  • 财政年份:
    2009
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Strategy for chemoprevention of digestive cancers by targeting abnormalities in receptor tyrosine kinases and nuclear receptors
针对受体酪氨酸激酶和核受体异常的消化道癌症化学预防策略
  • 批准号:
    19590720
  • 财政年份:
    2007
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Strategy for the chemoprevention of hepatocellular carcinoma by targeting phosphorylated RXRa
靶向磷酸化 RXRa 的肝细胞癌化学预防策略
  • 批准号:
    17015016
  • 财政年份:
    2005
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
The role of cytokine cascade in impaired liver regeneration and development of candidate pharmaceutical(s) to regulate this mechanism
细胞因子级联在肝脏再生受损中的作用以及调节该机制的候选药物的开发
  • 批准号:
    16590585
  • 财政年份:
    2004
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Retinoid upregulates the sensitivity of cancer cells to a cytokine by inducing the cytokine receptor
类维生素A通过诱导细胞因子受体上调癌细胞对细胞因子的敏感性
  • 批准号:
    13557048
  • 财政年份:
    2001
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
REGULATION OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID
无环维A酸对肝癌发生的调节作用
  • 批准号:
    11670490
  • 财政年份:
    1999
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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
  • 批准号:
    10557055
  • 财政年份:
    1998
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B).
GENOMIC MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY RETINOIDS
类维生素A调控肝癌发生的基因组机制
  • 批准号:
    05670463
  • 财政年份:
    1993
  • 资助金额:
    $ 1.6万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

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