| Project/Area Number |
07670552
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | ASAHIKAWA MEDICAL COLLEGE |
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Principal Investigator |
OBARA Takeshi ASAHIKAWA MEDICAL COLLEGE,THIRD DEPARTMENT OF INTERNAL MEDICINE,ASSOCIATE PROFESSOR, 医学部, 助教授 (60194627)
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| Co-Investigator(Kenkyū-buntansha) |
URA Hitoshi ASAHIKAWA MEDICAL COLLEGE,THIRD DEPARTMENT OF INTERNAL MEDICINE INSTRUCTOR, 医学部, 助手 (70280865)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1996: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1995: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | PANCREATIC CANCER / CHEMOTHERAPY / TARGET THERAPY / RAS / APOPTOSIS / p21 |
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| 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.
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