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MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID

Research Project

Project/Area Number 08670576
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionGIFU UNIVERSITY

Principal Investigator

MORIWAKI Hisataka  GIFU UNIVERSITY,SCHOOL OF MEDICINE,PROFESSOR, 医学部, 教授 (50174470)

Co-Investigator(Kenkyū-buntansha) OKUNO Masataka  GIFU UNIVERSITY,SCHOOL OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 助手 (10204140)
四童子 好広  岐阜大学, 医学部, 助手 (00111518)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsCANCER CHEMOPREVENTION / HEPATOCELLULAR CARCINOMA / RETINOID / RETINOID X RECEPTOR / DIFFERENTIATION INDUCTION / APOPTOSIS / CASPASE
Research Abstract

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.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Muto Y: "Prevention of second primary tumors by an acyclic retinoid,polyprenoic acid,in patients with hepatocellular carcinoma." N Engl J Med. 334. 1561-1567 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsushima-Nishiwaki R: "Aberrant metabolism of retinoid X receptor proteins in human hepatocellular carcinoma." Mol Cell Endocrinol. 121. 179-190 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsushima-Nishiwaki R: "Limited degradation of retinoid X receptor by calpain." Biochem Biophys Res Commun. 225. 946-951 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Moriwaki H: "Deletion of serum lectin-reactive α-fetoprotein by acyclic retinoid." Clin Cancer Res. 3. 727-731 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shidoji Y: "Rapid loss in the mitochondrial membrane potential during geranylgeranoic acid induced apoptosis." Biochem Biophys Res Commun. 230. 58-63 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuno M: "Retinoids exacerbate rat liver fibrosis by inducing the activation of laten TGF-β in liver stellate cells." Hepatology. 26. 911-921 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Muto Y.: "Prevention of second primary tumors by an acyclic retinoid,polyprenoic acid,in patients with hepatocellular carcinoma." Digestion. 59. 89-91 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuno M.: "Protease inhibitors suppress TGF-β generation by hepatic stelate cells." J.Hepatol.29. 1031-1032 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Muto Y.: "Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma" N Engl J Med. 印刷中. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuno M.: "Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis:Implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo" J.Hepatology. 印刷中. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Muto Y,Moriwaki H,Ninomiya M,et al.: "Prevention of second primary tumors by an acyclic retinoid, polyprenoicacid, in patients with hepatocellular carcinoma." N Engl J Med. 334. 1561-1567 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsushima-Nishiwaki R,Shidoji Y,Nishiwaki S,et al.: "Aberrant metabolism of retinoid X receptor proteins in human hepatocellular carcinoma." Mol Cell Endocrinol. 121. 179-190 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsushima-Nishiwaki R,Shidoji Y,Nishiwaki S,et al.: "Limited degradation of retinoid X receptor by calpan." Biochem Biophys Res Commun. 225. 946-951 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Moriwaki H,Yasuda I,Shiratori Y,et al.: "Deletion of serum lectin-reactive alpha-fetoprotein by acyclic retinoid." Clin Cancer Res. 3. 727-731 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shidoji Y,Nakamura N,Moriwaki H,et al.: "Rapid loss in the mitochondrial membrane potential during geranylgeranoic acid induced apoptosis." Biochem Biophys Res Commun. 230. 58-63 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuno M,Moriwaki H,Imai S,et al.: "Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells." Hepatology. 26. 911-921 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Muto Y,Moriwaki H,Shiratori Y.: "Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma." Digestion. 59. 89-91 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuno M.Moriwaki H,Muto Y.: "Protease inhibitors suppress TGF-beta generation by hepatic stelate cells." J.Hepatol. 29. 1031-1032 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuno M,Sato T,Kitamoto T.et al.: "Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis : Implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo" J.Hepatology. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Muto Y.: "Prevention of second primary tumors by an acyclic retinoid,polyprenoic acid,in patients with hepatocellular carcinoma." Digestion. 59. 89-91 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okuno M.: "Protease inhibitors suppress TGF-β generation by hepatic stellate cells." J.Hepatol.29. 1031-1032 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Muto Y.: "Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma" N Engl J Med. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okuno M.: "Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis : Implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo" J.Hepatology. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Muto Y: "Prevention of second primary tumors by an acyclic retinoid,polyprenoic acid,in patients with hepatocellular carcinoma." N Engl J Med. 334. 1561-1567 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsushima-Nishiwaki R: "Aberrant metabolism of retinoid X receptor proteins in human hepatocellular carcinoma." Mol Cell Endocrinol. 121. 179-190 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsushima-Nishiwaki R: "Limited degradation of retinoid X receptor by calpain." Biochem Biophys Res Commun. 225. 946-951 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Moriwaki H: "Deletion of serum lectin-reactive α-fetoprotein by acyclic retinoid." Clin Cancer Res. 3. 727-731 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Shidoji Y: "Rapid loss in the mitochondrial membrane potential during geranylgeranoic acid induced apoptosis." Biochem Biophys Res Commun. 230. 58-63 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Okuno M: "Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-β in liver stellate cells." Hepatology. 26. 911-921 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Muto Y: "Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma" N Engl J Med. 334. 1561-1567 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Matsushima-Nishiwaki R: "Aberabt metabolism of retinoid X receptor proteins in human hepatocellular carcinoma" Mol Cell Endocrinol. 121. 179-190 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Matsushima-Nishiwaki R: "Limited degradation of retinoid X receptor by calpain" Biochem Biophys Res Commun. 225. 946-951 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Moriwaki H: "Deletion of serum lectin-reactive α-fetoprotein by acyclic retinoid" Clin Cancer Res. 3(印刷中). (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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