title: The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus.
abstract: Oncolytic viral (OV) therapy has been considered as a promising treatment modality for brain tumors. Vasculostatin, the fragment of brain-specific angiogenesis inhibitor-1, shows anti-angiogenic activity against malignant gliomas. Previously, a vasculostatin-expressing oncolytic herpes simplex virus-1, Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO), was reported to have a potent antitumor effect. Here, we investigated the therapeutic efficacy of RAMBO and cilengitide, an integrin inhibitor, combination therapy for malignant glioma. In vitro, tube formation was significantly decreased in RAMBO and cilengitide combination treatment compared with RAMBO or cilengitide monotherapy. Moreover, combination treatment induced a synergistic suppressive effect on endothelial cell migration compared with the control virus. RAMBO, combined with cilengitide, induced synergistic cytotoxicity on glioma cells. In the caspase-8 and -9 assays, the relative absorption of U87ΔEGFR cell clusters treated with cilengitide and with RAMBO was significantly higher than that of those treated with control. In addition, the activity of caspase 3/7 was significantly increased with combination therapy. In vivo, there was a significant increase in the survival of mice treated with combination therapy compared with RAMBO or cilengitide monotherapy. These results indicate that cilengitide enhanced vasculostatin-expressing OV therapy for malignant glioma and provide a rationale for designing future clinical trials combining these two agents.
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Kurozumi
authors.forename: T
authors.initials: T
authors.lastname: Ichikawa
authors.forename: M
authors.initials: M
authors.lastname: Onishi
authors.forename: Y
authors.initials: Y
authors.lastname: Shimazu
authors.forename: J
authors.initials: J
authors.lastname: Ishida
authors.forename: E A
authors.initials: EA
authors.lastname: Chiocca
authors.forename: B
authors.initials: B
authors.lastname: Kaur
authors.forename: I
authors.initials: I
authors.lastname: Date
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D005910:Glioma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D012910:Snake Venoms / Q000494:pharmacology*; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: C468226:ADGRB1 protein, human; D042501:Angiogenic Proteins; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D012910:Snake Venoms; C422910:Cilengitide