title: Antiangiogenic therapy against experimental glioblastoma using genetically engineered cells producing interferon-alpha, angiostatin, or endostatin.
abstract: Inhibition of angiogenesis has been considered among the most promising approaches to treat highly vascularized solid tumors such as glioblastoma. In this study, we designed and validated a new in vitro assay system based on the implantation of tumor cells into organotypic brain slice cultures. We evaluated the effects of local production of three endogenous inhibitors of angiogenesis, angiostatin, endostatin, and interferon (IFN)-alpha(1), using stably transfected rat (9L) and human (GL15) glioblastoma cells on tumor vascularization and growth. Despite similar effectiveness of the three proteins in a classic in vitro endothelial cell migration assay, IFN-alpha(1) demonstrated the most potent antiangiogenic effect in organotypic brain slice cultures. In vivo, after intracerebral implantation of such genetically modified glioblastoma cells, IFN-alpha(1) caused a dramatic decrease in tumor volume revealed by magnetic resonance imaging and by postmortem histology. The mechanisms of this antitumor effect were most likely caused by the major antiangiogenic action of the cytokine, because IFN-alpha(1) expression provoked a pronounced decrease in blood vessel density, which was accompanied by extensive necrosis in the body mass of the tumors. The median survival time of rats implanted intracerebrally with IFN-alpha-expressing 9L cells tripled, and was still significantly increased when these constituted only 1% of transplanted tumor cells. A similar effect was seen when 50% of the transplanted cells were replaced by IFN-alpha-expressing bone marrow stromal cells. These data point to the local delivery of IFN-alpha(1) using cell vectors as a potent tool for the inhibition of tumor-induced angiogenesis.
authors.affiliation: INSERM U 421, Neuroplasticity and Therapeutics, Faculté de Médecine, 8 rue du Général Sarrail, 94010 Créteil, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: De Boüard
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Guillamo
authors.forename: Christo
authors.initials: C
authors.lastname: Christov
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lefévre
authors.forename: Pierre
authors.initials: P
authors.lastname: Brugières
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gola
authors.forename: Pauline
authors.initials: P
authors.lastname: Devanz
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
mesh_terms: D020533:Angiogenesis Inhibitors / Q000032:analysis; D043168:Angiostatins; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis / Q000235:genetics*; D043169:Endostatins; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016898:Interferon-alpha / Q000032:analysis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D010446:Peptide Fragments / Q000032:analysis / Q000235:genetics*; D010958:Plasminogen / Q000032:analysis / Q000235:genetics*; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D016898:Interferon-alpha; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen