Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence

Tumor angiogenesis involves a combination of events including the production of inhibitors, proteases, and angiogenic factors that have a chemotactic and mitogenic effect on endothelial cells. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that promotes angiogenesi...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1996-01, Vol.56 (2), p.393-401
Main Authors: Saleh, M, Stacker, S A, Wilks, A F
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Brain Neoplasms - blood supply
Brain Neoplasms - pathology
Brain Neoplasms - therapy
Cell Division - physiology
Cell Hypoxia
Cloning, Molecular
DNA, Complementary - genetics
Endothelial Growth Factors - biosynthesis
Endothelial Growth Factors - genetics
Endothelial Growth Factors - physiology
Endothelium, Vascular - growth & development
Endothelium, Vascular - physiology
Female
Genetic Therapy
Glioma - blood supply
Glioma - pathology
Glioma - therapy
Lymphokines - biosynthesis
Lymphokines - genetics
Lymphokines - physiology
Male
Mice
Mice, Nude
Molecular Sequence Data
Necrosis
Neovascularization, Pathologic - therapy
Oligonucleotides, Antisense - genetics
Rats
Transfection
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
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Summary:Tumor angiogenesis involves a combination of events including the production of inhibitors, proteases, and angiogenic factors that have a chemotactic and mitogenic effect on endothelial cells. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that promotes angiogenesis in solid tumors, including brain tumors such as astrocytomas. As an approach to the development of new strategies for gene therapy of brain tumors, we have interrupted the VEGF/VEGF receptor paracrine pathway in an attempt to inhibit angiogenesis and thereby control tumor growth. Rat C6 glioma cells were transfected with a eukaryotic expression vector bearing an antisense-VEGF cDNA. Stable transfectants were observed to express reduced levels of VEGF in culture under hypoxic conditions. When implanted s.c. into nude (nu/nu) mice, growth of the antisense-VEGF cell lines was observed to be greatly inhibited compared to control cells, despite the fact that they have a faster division time in vitro. Analysis of these tumors revealed that they have fewer blood vessels and a higher degree of necrosis, which is a plausible explanation for the reduced tumor size. We believe antisense-VEGF can be successfully used to control tumor growth and may provide the basis for the development of antiangiogenic gene therapy.
ISSN:0008-5472