title: Sorafenib tosylate as a radiosensitizer in malignant astrocytoma.
abstract: Progress in research on the molecular aspects of glioblastoma has yet to provide a medical therapy that significantly improves prognosis. Glioblastoma invariably progress through current treatment regimens with radiotherapy as a key component. Activation of several signaling pathways is thought to be associated with this resistance to radiotherapy. Ras activity is exceptionally high in glioblastoma and may regulate sensitivity to radiotherapy. Raf-1, a downstream effector of Ras, demonstrates a high amount of activity in glioblastoma. Therefore, Raf-1 inhibition should be considered as a mechanism to increase the effectiveness of radiotherapy in treatment regimen. In vitro analysis was performed with a novel Raf-1 kinase inhibitor (BAY 54-9085) in culture with the glioblastoma cell line U1242. The cell line was treated in serum-containing media and analyzed for the effect of the BAY 54-9085 alone and BAY 54-9085 combined with radiation on cell death. BAY 54-9085 displayed a cytocidal effect on glioblastoma cells following a 3 day incubation with the drug in serum-containing media. A dose of 2.5 μM displayed moderate cell death which significantly increased with a dose of 5.0 μM. In addition, glioblastoma cells treated with both the BAY 54-9085 and gamma radiation displayed a significant increase in cell death (85.5%) as compared to either BAY 54-9085 (73.1%) or radiation (34.4%) alone. Radiation therapy is a key component of treatment for glioblastoma. A novel Raf-1 inhibitor displayed in vitro evidence of synergistically increasing cell death of glioblastoma cells in combination with radiation.
authors.affiliation: Department of Neurosurgery, The George Washington University, 2150 Pennsylvania Avenue, NW, Suite 7-420, Washington, DC 20037, USA. Electronic address: jsherman0620@gmail.com.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Sherman
authors.affiliation: School of Medicine, The George Washington University, Washington, DC, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Kirzner
authors.affiliation: Department of Neurosurgery, The George Washington University, 2150 Pennsylvania Avenue, NW, Suite 7-420, Washington, DC 20037, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Siu
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Samson
authors.initials: S
authors.lastname: Amos
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Isa M
authors.initials: IM
authors.lastname: Hussaini
mesh_terms: D001254:Astrocytoma / Q000473:pathology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D010671:Phenylurea Compounds; D011838:Radiation-Sensitizing Agents; D009536:Niacinamide; D000077157:Sorafenib
keywords: Malignant astrocytoma; Radiosensitizer; Sorafenib