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1993 Fiscal Year Final Research Report Summary

Cancer therapy by way of inhibition of farnesylation of ras proteins

Research Project

Project/Area Number 03670354
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionUNIVERSITY OF TOKYO

Principal Investigator

MATSUHASHI Nobuyuki  UNIVERSITY OF TOKYO,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部(病), 助手 (10221590)

Co-Investigator(Kenkyū-buntansha) OHNISHI Shin  UNIVERSITY OF TOKYO,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部(病), 助手 (00183236)
KODAMA Tatsuhiko  UNIVERSITY OF TOKYO,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 助手 (90170266)
Project Period (FY) 1991 – 1993
Keywordsras / farnesyl / cancer / mevalonate / HMG-CoA reductase / cholesterol
Research Abstract

In search of a new canther thrapy, we investigated whether cancer therapy is possible by way of inhibiting ras protein farnesylation. In the first series of experiments, we investigated what factors derived from mevalonate, except for cholesterol, are essential for cell growth. We supposed that farnesyl moiety derived from farnesyl-pyrophosphate is the putative factor, and we tried to prove this hypothesis. In cell culture experiments, compactin, an HMG-CoA reductase inhibitor, suppressed the growth of every cell line tested, and the degree of growth suppress was similar in ras-mutated cell lines and non-ras-mutated ones. We noticed that mevalonate fails to recover the cell growth suppressive effect of HMG-CoA reductase inhibitors. From these results, we cannot couclude that the cell growth inhibiting effect of compactin is mediated by expression blockade of ras proteins. A synthetic tetrapeptide (CVIM), which represents a common motif in the C-terminus of ras proteins and is known to competetively inhibit farnesyl : protein transferase, was synthethized and was used in cell culture system, but the peptide failed to pass through the cell membrane and we could not obtain results.
As an in vivo study, we tried to see whether a HMG-CoA reductase inhibitor can prevent cancer occurrence in a spontaneously-occurring mouse cancer system. Simvastatin was given to C3H mice. However, we failed to demonstrate significant cancer preventing effects of the agent. Finally, a small clinical therapy trial was conducted in which three advanced cancer patients were treated with pravastatin. We failed to demonstrate significant anti-cancer effects in those patients. Thus, we could not obtain evidence that inhibition of ras protein farnesylation can mediate anti-tumor effects in this system. Further investigations will be necessary using specific farnesyl : protein transferase inhibitors.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Fukushima Y, Matsuhashi N,et al: "Expression of histamine H2 receptor in Chinese hamster ovary cells" J Gastroenterol. 29. 68-72 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fukushima Y, Matsuhashi N,et al: "Desensitization of canine histamine H2 receptor expressed in Chinese hamster ovary cells" Biochem Biophys Res Comm. 190. 1149-1155 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sugano K, Matsuhashi N,et al: "Negative feedback regulation of acid secretion" GastroenterologiaJaponica. 28. 118-121 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sugano K, Matsuhashi N,et al: "Studies o histamine receptors in rabbit parietal cells" Gastrointest Function. 2. 101-113 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsuhashi N, Yamada A et al: "Multiple strictures of the small intestine after long-term non-steroidal anti-inflammatory drug therapy" Am J Gastroenterol. 87. 1183-1186 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Gunji T, Matsuhashi N et al: "Treatment of hepatocellular carcinoma associated with advanced cirrhosis by transcatheter arterial chemoembolization" Hepatology. 15. 252-257 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsuhashi N, Kawase Y et al: "Tolerogenic ability of thymocytes in organ-cultured thymus lobes" J Immunol. 146. 444-448 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kimura W,Matsuhashi N,et al.: "Pancreatic carcinoma accompanied by pseudocyst : report of two cases." J Gastroenterol. 29. 786-791 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Gatanaga H,Matsuhashi N,et al.: "Retroperitoneal fibrosis leading to extrahepatic portal vein obstruction." Int.Med. 33. 346-350 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fukushima Y,Matsuhashi N,et al.: "Expression of histamine H2 receptor in Chinese hamster ovary cells : a probe to study the desensitization mechanism." J Gastroenterol. 29. 68-72 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fukushima Y,Matsuhashi N,et al.: "Desensitization of canine histamine H2 receptor expressed in Chinese hamster ovary cells." Biochem Biophys Res Comm. 190. 1149-1155 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sugano K,Matsuhashi N,et al.: "Negative feedback regulation of acid secretion : linkage of acid secretion and mucosal defense." Gastroenterol Jpn. 28. 118-121 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sugano K,Matsuhashi N,et al.: "Studies on histamine receptors in rabbit parietal cells." Gastrointest Function. 2. 101-113 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsuhashi N,Yamada A,et al.: "Multiple strictures of the small intestine after long-term non-steroidal anti-inflammatory drug therapy." Am J Gastroent. 87. 1183-1186 (1992)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-16  

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