title: Synergistic antiglioma activity of radiotherapy and enzastaurin.
abstract: OBJECTIVE
  Radiotherapy is an essential treatment modality for malignant gliomas, but it exerts adverse effects via promotion of glioma cell invasion in experimental glioma. Furthermore, irradiation induces vascular endothelial growth factor (VEGF) levels in gliomas, which is associated with poor prognosis. Here, we investigate the combination of the protein kinase C-beta inhibitor enzastaurin (ENZA) and radiotherapy in vitro and in vivo in comparison with either treatment alone.
  
  
  METHODS
  We analyzed the effects of ENZA and irradiation on migration, apoptosis, and proliferation of glioma cells, as well as VEGF secretion in vitro. Neurotoxicity of ENZA was assessed in cerebellar granule neurons. After orthotopic intracerebral implantation of LNT-229 glioma cells in nude mice, the effects of in situ cerebral irradiation and oral application of ENZA on survival, tumor size, VEGF expression, apoptosis, and microvessel density in vivo were analyzed.
  
  
  RESULTS
  Combining cerebral irradiation with ENZA leads to longer survival in vivo. ENZA diminishes tumor volume, irradiation-induced tumor satellite formation, upregulation of VEGF expression in vitro and in vivo, as well as enhanced microvessel density in vivo. Importantly, ENZA is not neurotoxic in vitro or in vivo.
  
  
  CONCLUSIONS
  Long-term administration of ENZA after radiotherapy is feasible and leads to long-term survival without neurotoxicity.
authors.affiliation: Laboratory of Molecular Neurooncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University of Tübingen, Germany.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Tabatabai
authors.forename: Brigitte
authors.initials: B
authors.lastname: Frank
authors.forename: Antje
authors.initials: A
authors.lastname: Wick
authors.forename: Dieter
authors.initials: D
authors.lastname: Lemke
authors.forename: Gabriele
authors.initials: G
authors.lastname: von Kürthy
authors.forename: Ulrike
authors.initials: U
authors.lastname: Obermüller
authors.forename: Stefan
authors.initials: S
authors.lastname: Heckl
authors.forename: Gunter
authors.initials: G
authors.lastname: Christ
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D005910:Glioma / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology / Q000532:radiotherapy*; D007211:Indoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016019:Survival Analysis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin