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RESEARCH ARTICLE
The growth inhibition of hepatoma by gene
transfer of antisense vascular endothelial
growth factor
Mi Ae Kang
Kye Young Kim
Ji Yeon Seol
Kyu Chan Kim
Myeong Jin Nam*
Cancer Research Division, National
Institute of Health, Nokbun-dong 5.
Eunpung-ku, Seoul 122-701, Korea
*Correspondence to: M. J. Nam,
Cancer Research Division, National
Institute of Health, Nokbun-dong 5,
Eunpung-ku, Seoul 122-701, Korea.
E-mail: genetx@hanmail.net
Received: 7 February 2000
Revised: 10 April 2000
Accepted: 18 April 2000
Published online: 27 April 2000
Abstract
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.
Method 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 ®brin 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
signi®cantly suppressed tubule formation of BCE cells. pZeoVEGFa inhibited
a morphological change from a round shape to an elongated spindle shape in
®brin gel. When pZeoVEGFa was injected peritumorally by liposomes, tumor
growth was inhibited.
Conclusion Endothelial cell proliferation, tubule formation and tumor
growth may be diminished by down-regulation of endogenous VEGF
expression in tumor cells or tissue. These ®ndings indicate that the ef®cient
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. Copyright # 2000 John Wiley & Sons, Ltd.
Keywords VEGF; hepatoma; antisense; gene therapy
Introduction
Angiogenesis is a complex process involving a cascade of events that result in
the formation of new blood vessels. Such vessel formation takes place under
both normal physiological conditions, such as embryogenesis, ovulation, and
wound healing, as well as pathological ones, including tumor neovascular-
ization and retinopathies [1,2]. In particular, it is important for the
proliferation and metastasis of solid tumors [3]. In the avascular phase,
tumor masses are no more than a few millimeters in diameter [4]. After
capillarization, tumors rapidly grow into large masses [5]. Extensive
experimental and clinical data exist to support the concept that growth of
THE JOURNAL OF GENE MEDICINE
J Gene Med 2000; 2: 289±296.
Copyright # 2000 John Wiley & Sons, Ltd.