Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma.
Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.
Ohlfest
John R
JR
Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
Demorest
Zachary L
ZL
Motooka
Yasuhiko
Y
Vengco
Isabelita
I
Oh
Seunguk
S
Chen
Eleanor
E
Scappaticci
Frank A
FA
Saplis
Rachel J
RJ
Ekker
Stephen C
SC
Low
Walter C
WC
Freese
Andrew B
AB
Largaespada
David A
DA
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000627:therapeutic use*; D043168:Angiostatins / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D004251:DNA Transposable Elements; D043169:Endostatins / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008156:Luciferases / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010957:Plasmids / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D014183:Transplantation, Heterologous; D019895:Transposases / Q000235:genetics
D020533:Angiogenesis Inhibitors; D004251:DNA Transposable Elements; D043169:Endostatins; D043168:Angiostatins; D008156:Luciferases; D040262:Receptors, Vascular Endothelial Growth Factor; D019895:Transposases; C494471:sleeping beauty transposase, human