title: Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: from bedside to bench.
abstract: Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival.
authors.affiliation: Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68th Street, Box 99, New York, NY 10021, USA.
authors.forename: Jan-Karl
authors.initials: JK
authors.lastname: Burkhardt
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Hofstetter
authors.forename: Alejandro
authors.initials: A
authors.lastname: Santillan
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Shin
authors.forename: Conor P
authors.initials: CP
authors.lastname: Foley
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Ballon
authors.forename: Y
authors.initials: Y
authors.lastname: Pierre Gobin
authors.forename: John A
authors.initials: JA
authors.lastname: Boockvar
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy*; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005909:Glioblastoma / Q000188:drug therapy*; D007150:Immunohistochemistry; D007269:Injections, Intra-Arterial; D049449:Luminescence; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods*; D014411:Neoplastic Stem Cells; D013238:Stereotaxic Techniques; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab