Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy.
Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.
Nguyen
J T
JT
Department of Radiological Sciences, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Wu
P
P
Clouse
M E
ME
Hlatky
L
L
Terwilliger
E F
EF
D043168:Angiostatins; D003094:Collagen / Q000235:genetics*; D017077:Culture Media, Conditioned; D000229:Dependovirus / Q000235:genetics; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D008222:Lymphokines / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics*; D010958:Plasminogen / Q000235:genetics*; D016372:RNA, Antisense / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017077:Culture Media, Conditioned; D043169:Endostatins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D016372:RNA, Antisense; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen