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- W2805541979 abstract "3805 Sarcomas are a heterogeneous group of mesenchymal malignancies whose benefit from traditional chemotherapy has been maximized. A diagnosis of sarcoma still portends a poor prognosis with a disease specific mortality of up to 50%. Sarcomas are fertile ground for the application of novel, targeted therapies with the hope of identifying a treatment effective across histologic subtypes. We report that farnesyltransferase inhibitors (FTIs) demonstrate in vitro activity against sarcoma cell lines of variable histologies. Seven different sarcoma subtypes, including osteosarcoma, synovial sarcoma, uterine sarcoma and Ewing’s sarcoma were examined for their sensitivity to two FTI compounds, BMS214662 and BMS225975. Both compounds demonstrated exquisite growth inhibition as detected by cell count and MTT assays. IC50’s were in the range of 125-400 nanomolars, concentrations known to inhibit farnesylation. FTIs inhibited cellular growth in every histology tested. This is in contrast to other signal transduction inhibitors, i.e. of the MAPK pathway, whose effects were limited to specific pathologies alone. BMS214662 and BMS225975 differ in their potency and mechanism of action, providing an accurate tool to evaluate reasons for their efficacy. In most cell lines, FACS analysis showed an accumulation in the G1 phase of the cell cycle with little or no increase in apoptosis. Investigations of signaling properties after exposure to FTI revealed inhibition of S6 phosphorylation in some cell lines in a fashion similar to that seen with the use of rapamycin. S6 is a downstream effector of mTOR. The activation of mTOR/S6K relies on the farnesylation of Rheb. These results suggest that FTIs may inhibit the growth of some of our sarcoma cell lines by down regulating the TSC/Rheb/mTOR pathway. Effects of combining FTIs with other reagents such as taxanes are currently being investigated. These results are forthcoming and will be discussed." @default.
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- W2805541979 date "2006-04-15" @default.
- W2805541979 modified "2023-09-28" @default.
- W2805541979 title "Promising activity of farnesyltransferase inhibitors across seven different sarcoma subtypes" @default.
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