title: 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.
abstract: 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.
authors.affiliation: Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Demorest
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Motooka
authors.forename: Isabelita
authors.initials: I
authors.lastname: Vengco
authors.forename: Seunguk
authors.initials: S
authors.lastname: Oh
authors.forename: Eleanor
authors.initials: E
authors.lastname: Chen
authors.forename: Frank A
authors.initials: FA
authors.lastname: Scappaticci
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Saplis
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ekker
authors.forename: Walter C
authors.initials: WC
authors.lastname: Low
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Freese
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: 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
chemical_list: 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