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• W2093582906 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 farnesylamine, one of the FPTase inhibitors (FTI), is selectively cytotoxic in pancreatic carcinoma cells and Ki-ras–transformed fibroblasts. Furthermore, we investigated whether the cytotoxicity of farnesylamine is caused by 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, 24 and 5 μM farnesylamine were required to achieve 50% cytotoxicity in pancreatic carcinoma cells containing activated Ki-ras and Ki-ras–transformed NIH/3T3 cells, respectively. The parental NIH/3T3 cells were resistant to the cytotoxic effect of farnesylamine at concentrations less than 100 μM. After incubation with farnesylamine, DNA fragmentation was observed in both pancreatic carcinoma cells and Ki-ras–transformed fibroblasts at cytotoxic doses of this compound but not in NIH/3T3 cells. These results indicate that the mechanism of cell death induced by farnesylamine is apoptosis, and this apoptosis occurred specifically in pancreatic carcinoma cells containing mutated Ki-ras and the Ki-ras–transformed cells. Because raf is downstream of ras (p21ras) in the ras–raf–mitogen-activated protein 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 that very frequently contain a Ki-ras oncogene mutation, e.g., pancreatic cancer. Mol. Carcinog. 21:93–99, 1998. © 1998 Wiley-Liss, Inc." @default.
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• W2093582906 date "1998-02-01" @default.
• W2093582906 modified "2023-09-30" @default.
• W2093582906 title "Selective cytotoxicity of farnesylamine to pancreatic carcinoma cells and Ki-ras–transformed fibroblasts" @default.
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• W2093582906 doi "https://doi.org/10.1002/(sici)1098-2744(199802)21:2<93::aid-mc3>3.0.co;2-p" @default.
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