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Synergistic antiglioma activity of radiotherapy and enzastaurin
Author(s) -
Tabatabai Ghazaleh,
Frank Brigitte,
Wick Antje,
Lemke Dieter,
von Kürthy Gabriele,
Obermüller Ulrike,
Heckl Stefan,
Christ Gunter,
Weller Michael,
Wick Wolfgang
Publication year - 2007
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21057
Subject(s) - in vivo , glioma , neurotoxicity , cancer research , radiation therapy , medicine , apoptosis , in vitro , pharmacology , chemistry , biology , toxicity , biochemistry , microbiology and biotechnology
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‐β 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. Interpretation Long‐term administration of ENZA after radiotherapy is feasible and leads to long‐term survival without neurotoxicity. Ann Neurol 2007