Synergistic antiglioma activity of radiotherapy and enzastaurin.
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.
Tabatabai
Ghazaleh
G
Laboratory of Molecular Neurooncology, Department of General Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University of Tübingen, Germany.
Frank
Brigitte
B
Wick
Antje
A
Lemke
Dieter
D
von Kürthy
Gabriele
G
Obermüller
Ulrike
U
Heckl
Stefan
S
Christ
Gunter
G
Weller
Michael
M
Wick
Wolfgang
W
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
D007211:Indoles; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin