title: Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adeno-associated viral (AAV) vector.
abstract: We have utilized a recombinant adeno-associated viral (AAV) vector carrying the angiostatin gene as an anti-angiogenesis strategy to treat the malignant brain tumor in a C6 glioma/Wistar rat model. Angiostatin, as a potent angiogenesis inhibitor, shows high promises as an anti-cancer drug through the inhibition of tumor neovessel formation. However, sustained in vivo protein delivery is required to achieve the therapeutic effects. The AAV vector has been proven to be able to deliver sustained and high-level gene expression in vivo, and therefore, is well suited to such a purpose. In this study, we implanted 5 x 10(5) C6 glioma cells into the rat brain 7 days before gene therapy. Intratumoral injection of a high-titer AAV-angiostatin vector has rendered efficacious tumor suppression and resulted in long-term survival in 40% of the treated rats, whereas the control AAV-GFP vector did not have any therapeutic benefits. In addition, we have investigated the combined gene therapy of an adenoviral vector carrying the suicidal thymidine kinase gene along with the AAV-angiostatin vector. The combined therapy offered the best tumor-suppressive effects and increased long-term survival to 55% in the treated rats. Our study has demonstrated the potential of using AAV as a safe and effective vector for anti-angiogenic gene therapy of brain tumors.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: H-I
authors.initials: HI
authors.lastname: Ma
authors.forename: S-Z
authors.initials: SZ
authors.lastname: Lin
authors.forename: Y-H
authors.initials: YH
authors.lastname: Chiang
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: S-L
authors.initials: SL
authors.lastname: Chen
authors.forename: Y-P
authors.initials: YP
authors.lastname: Tsao
authors.forename: X
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000627:therapeutic use*; D043168:Angiostatins; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D005910:Glioma / Q000628:therapy*; D015552:Injections, Intralesional; D008297:Male; D023421:Models, Animal; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics / Q000627:therapeutic use*; D010958:Plasminogen / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen; D013937:Thymidine Kinase