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. Neurotoxiciuy 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. Interpretation: Long-term administration of ENZA after radiotherapy is feasible and leads to long-term survival without neurotoxicity.