Suppression of intracranial human glioma growth after intramuscular administration of an adeno-associated viral vector expressing angiostatin.
Despite various therapeutic interventions, glioblastoma multiforme (GBM) is one of the most highly vascularized neoplasms in humans with poor prognosis. In this study, we show that a single i.m. injection of an adeno-associated viral (AAV) vector expressing angiostatin, a potent angiogenic inhibitor, effectively suppresses human glioma growth in the brain of nude mice. Approximately 40% of the tumor-bearing mice treated with AAV-angiostatin vector survived for >10 months (the duration of the experiments). In contrast, 100% of the tumor-bearing mice in the control groups, with or without i.m. injection of a control vector AAV-GFP, died because of excessive tumor burden by 6 weeks. High levels of angiostatin produced by the AAV vector were detected in blood circulation for >250 days after the one-time vector injection. The secreted angiostatin specifically targeted neovessels in the brain tumors, as evidenced by the diminished vessel densities and increased apoptosis of tumor cells surrounding these neovessels. Our study thus demonstrates that AAV-mediated antiangiogenesis gene therapy offers efficient and sustained systemic delivery of the therapeutic product, which in turn effectively suppresses glioma growth in the brain.
Ma
Hsin-I
HI
Cancer Institute and Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Guo
Ping
P
Li
Juan
J
Lin
Shinn-Zong
SZ
Chiang
Yung-Hsiao
YH
Xiao
Xiao
X
Cheng
Shi-Yuan
SY
D000256:Adenoviridae / Q000235:genetics; D043168:Angiostatins; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000502:physiology; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy; D010446:Peptide Fragments / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D010958:Plasminogen / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen