Development of lentiviral vectors for antiangiogenic gene delivery.
Growth and metastasis of malignant tumors requires angiogenesis. Inhibition of tumor-induced angiogenesis may represent an effective cytostatic strategy. We have constructed recombinant self-inactivating lentiviral vectors expressing angiostatin and endostatin, and have tested their antiangiogenic activities. As VSV-G-pseudotyped lentiviral vectors showed low relative transduction titers on bovine aortic and human umbilical vein endothelial cells, it was difficult to achieve significant inhibition of endothelial cell growth by lentivirus-mediated antiangiogenic gene transfer directly to endothelial cells without concomitant vector-associated cytotoxicity. However, lentivirus vectors could efficiently and stably transduce T24 human bladder cancer cells that are relatively resistant to adenovirus infection due to loss of coxsackievirus-adenovirus receptor expression. Long-term expression and secretion of angiostatin and endostatin from lentivirus-transduced T24 cells resulted in significant inhibition of cellular proliferation on coculture with endothelial cells. This report represents the first use of lentivirus-based vectors to deliver the antiangiogenic factors, angiostatin and endostatin, and suggests the potential utility of antiangiogenic gene therapy with lentiviral vectors for the treatment of cancer.
Shichinohe
T
T
Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Bochner
B H
BH
Mizutani
K
K
Nishida
M
M
Hegerich-Gilliam
S
S
Naldini
L
L
Kasahara
N
N
D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000235:genetics*; D043168:Angiostatins; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002470:Cell Survival; D018920:Coculture Techniques; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000628:therapy; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000502:physiology
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen