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1997 Fiscal Year Final Research Report Summary

TARGET THERAPY OF RAS ONCOGENE PROTEIN PRODUCT IN PANCREATIC CANCER

Research Project

Project/Area Number 07670552
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionASAHIKAWA MEDICAL COLLEGE

Principal Investigator

OBARA Takeshi  ASAHIKAWA MEDICAL COLLEGE,THIRD DEPARTMENT OF INTERNAL MEDICINE,ASSOCIATE PROFESSOR, 医学部, 助教授 (60194627)

Co-Investigator(Kenkyū-buntansha) URA Hitoshi  ASAHIKAWA MEDICAL COLLEGE,THIRD DEPARTMENT OF INTERNAL MEDICINE INSTRUCTOR, 医学部, 助手 (70280865)
Project Period (FY) 1995 – 1997
KeywordsPANCREATIC CANCER / CHEMOTHERAPY / TARGET THERAPY / RAS / APOPTOSIS
Research Abstract

Farnesyl protein transferase (FPTase) catalyses the post-translational modification of proteins by a farnesyl pyrophosphate. One of the substrates of this enzyme is p21ras, the product of the ras oncogene. We examined whether the cytotoxic effects of farnesylamine, one of the FPTase inhibitors (FTI), is selective in pancreatic carcinoma cells and K-ras transformed fibroblasts.
Furthermore, we investigated whether the cytotoxicity of farnesylamine is due to the induction of apoptosis in these cells.
Using the FPTase assay, we found that farnesylamine inhibited FPTase in vitro. Immunoprecipitation showed that farnesylamine inhibited farnesylation of p21ras in vivo. In addition, 9-28muM of farnesylamine were required to achieve 50% cytotoxicity in pancreatic carcinoma cells containing activated K-ras, and K-ras transformed NIH3T3 cells. The parental NIH3T3 cells were resistant to the cytotoxic effect of farnesylamine at concentrations under 100muM.After incubation with farnesylamine, DNA fragmentation was observed in both pancreatic carcinoma cells and K-ras transformed fibroblasts at cytotoxic doses of this compound, but not in NIH3T3 cells.
These results indicate that the mechanism of cell death induced by farnesylamine is apoptosis and the apoptosis occurred specifically in pancreatic carcinoma cells containing mutated K-ras and the K-ras transformed cells. Since Raf is downstream for the Ras (p21ras) in Ras-Raf-MAP kinase signaling pathway, we used c-raf-1 transformed fibroblasts, which proved to be resistant to apoptosis induced by farnesylamine. This supports the theory that inhibition of Ras signaling may be related to the induction of apoptosis. These data further suggest that farnesylamine could be useful as a chemotherapeutic agent in cancers, such as those of the pancreas, that very frequently contain K-ras oncogene mutation.

  • Research Products

    (11 results)

All Other

All Publications (11 results)

  • [Publications] Ura H, et al.: "Cytotoxicity of simvastatin to pancreatic adenocarcinoma cells containing mutant rasgene" Jpn J Cancer Res. 85. 633-638 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 小原 剛, 他: "Farnesyl Trasnferase阻害剤によるヒト膵癌細胞とras形質転換細胞のアポトーシス誘導" Biotherapy. 10・3. 286-288 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] B.A.Ruggeri, et al: "Molecular pathology of primary and metastatic pancreatic lesions;Analysis of mutations and expression of the p53.mdm-2.and........" Cancer. 79・4. 700-716 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 首藤 龍人, 他: "膵癌におけるシスプラチンのアポトーシス誘導に及ぼすカフェインの効果" 膵臓. 21・4. 355-361 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 浦 等, 他: "膵癌細胞における蛋白farnesyl化によるアポトーシス誘導" 消化器癌の発生と進展. 9. 67-68 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ura H, et al: "Farnesylamine is selectively cytotoxicto pancreatic carcinoma cells and k-ras transformed fibroblast" Molecular Carcinogenesis. (in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ura H,et al.: "Cytotoxicity of simvastatin to pancreatic adenocarcinoma cells containing mutant ras gene." Jpn J Cancer Res. 85. 633-638 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Obara T,et al.: "Induction of apoptosis by farnesyl transferase inhibitors (FTIs) in human pancreatic carcinoma cells and ras-transformed fibroblasts." Biotherapy. 10 (3). 286-288 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] B.A.Ruggeri, et al.: "Molecular pathology of primary and metastatic pancreatic lesions ; Analysis of mutations and expression of the p53, mdm-2, and p21/WAF-1 genes in sporadic and familial lesions" Cancer. 79 (4). 700-716 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shudo R et al.: "Combined effect of caffein and cisplatin on the induction of apoptosis in pancreatic adenocarcinoma cell lines." J JPN PAN SOC. 21 (4). 355-361 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ura H,et al.: "Farnesylamine is selectively cytotoxic to pancreatic carcinoma cells and k-ras transformed fibroblast." Molecular Carcinogenesis. (in press). (1998)

    • 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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