The growth inhibition of hepatoma by gene transfer of antisense vascular endothelial growth factor.
BACKGROUND
Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis and tumor growth in solid tumors. Therefore, to induce tumor regression, antiangiogenic agents to block VEGF need to be administered repeatedly.


METHODS
We constructed the recombinant mammalian expression vector bearing an antisense-VEGF cDNA, pZeoVEGFa. We examined the effect of pZeoVEGFa on the growth of SK-HEP1 hepatoma cells, bovine capillary endothelial (BCE) cells, and tubule formation of BCE cells in fibrin gel. To evaluate the function of pZeoVEGFa in vivo, we implanted SK-HEP1 hepatoma cells subcutaneously into nude mice.


RESULTS
In SK-HEP1 hepatoma cells, we showed that the synthesis of VEGF protein was suppressed by the stable and transient transfection of pZeoVEGFa. pZeoVEGFa inhibited the proliferation of BCE cells and significantly suppressed tubule formation of BCE cells. pZeoVEGFa inhibited a morphological change from a round shape to an elongated spindle shape in fibrin gel. When pZeoVEGFa was injected peritumorally by liposomes, tumor growth was inhibited.


CONCLUSIONS
Endothelial cell proliferation, tubule formation and tumor growth may be diminished by down-regulation of endogenous VEGF expression in tumor cells or tissue. These findings indicate that the efficient down-regulation of the VEGF produced by tumor cells using antisense strategies has an antitumor effect. We suggest that VEGF-targeted antiangiogenic gene therapy could be an effective strategy to treat VEGF-producing tumors.
Kang
M A
MA
Cancer Research Division, National Institute of Health, Seoul, Korea.
Kim
K Y
KY
Seol
J Y
JY
Kim
K C
KC
Nam
M J
MJ
D000818:Animals; D002196:Capillaries / Q000166:cytology; D006528:Carcinoma, Hepatocellular; D002417:Cattle; D002455:Cell Division; D002478:Cells, Cultured; D016373:DNA, Antisense / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008081:Liposomes; D008113:Liver Neoplasms; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016373:DNA, Antisense; D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008081:Liposomes; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors