title: Bevacizumab with angiostatin-armed oHSV increases antiangiogenesis and decreases bevacizumab-induced invasion in U87 glioma.
abstract: Bevacizumab (BEV) is an antiangiogenic drug approved for glioblastoma (GBM) treatment. However, it does not increase survival and is associated with glioma invasion. Angiostatin is an antiangiogenic polypeptide that also inhibits migration of cancer cells, but is difficult to deliver. Oncolytic viruses (OV) can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them and deliver anticancer agents to uninfected cells. We have tested a combination treatment of BEV plus an OV expressing angiostatin (G47Δ-mAngio) in mice-bearing human GBM. Using a vascular intracranial human glioma model (U87) in athymic mice, we performed histopathological analysis of tumors treated with G47Δ-mAngio or BEV alone or in combination, followed tumor response by magnetic resonance imaging (MRI), and assessed animal survival. Our results indicate that injection of G47Δ-mAngio during BEV treatment allows increased virus spread, tumor lysis, and angiostatin-mediated inhibition of vascular endothelial growth factor (VEGF) expression and of BEV-induced invasion markers (matrix metalloproteinases-2 (MMP2), MMP9, and collagen). This leads to increased survival and antiangiogenesis and decreased invasive phenotypes. We show for the first time the possibility of improving the antiangiogenic effect of BEV while decreasing the tumor invasive-like phenotype induced by this drug, and demonstrate the therapeutic advantage of combining systemic and local antiangiogenic treatments with viral oncolytic therapy.
authors.affiliation: Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Giulia
authors.initials: G
authors.lastname: Fulci
authors.forename: Jason S
authors.initials: JS
authors.lastname: Buhrman
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D043168:Angiostatins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007267:Injections; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D043168:Angiostatins