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

John R. Ohlfest, Zachary L. Demorest, Yasuhiko Motooka, Isabelita Vengco, Seunguk Oh, Eleanor Chen, Frank A. Scappaticci, Rachel J. Saplis, Stephen C Ekker, Walter C. Low, Andrew B. Freese, David A. Largaespada

Research output: Contribution to journalArticle

106 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)778-788
Number of pages11
JournalMolecular Therapy
Volume12
Issue number5
DOIs
StatePublished - Nov 2005
Externally publishedYes

Fingerprint

Beauty
Glioblastoma
Genetic Therapy
Glioma
Survival
Genes
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Neoplasms
Luciferases
Heterografts
Angiostatins
Endostatins
Transposases
Vascular Endothelial Growth Factor Receptor-1
Convection
Gene Fusion
DNA
Transgenes
Brain Neoplasms
Transfer (Psychology)

Keywords

  • Angiogenesis
  • Glioblastoma
  • Nonviral
  • Sleeping beauty
  • Transposon

ASJC Scopus subject areas

  • Molecular Biology

Cite this

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. / Ohlfest, John R.; Demorest, Zachary L.; Motooka, Yasuhiko; Vengco, Isabelita; Oh, Seunguk; Chen, Eleanor; Scappaticci, Frank A.; Saplis, Rachel J.; Ekker, Stephen C; Low, Walter C.; Freese, Andrew B.; Largaespada, David A.

In: Molecular Therapy, Vol. 12, No. 5, 11.2005, p. 778-788.

Research output: Contribution to journalArticle

Ohlfest, John R. ; Demorest, Zachary L. ; Motooka, Yasuhiko ; Vengco, Isabelita ; Oh, Seunguk ; Chen, Eleanor ; Scappaticci, Frank A. ; Saplis, Rachel J. ; Ekker, Stephen C ; Low, Walter C. ; Freese, Andrew B. ; Largaespada, David A. / 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. In: Molecular Therapy. 2005 ; Vol. 12, No. 5. pp. 778-788.
@article{24c841d9fe4e49729cb22944c47845ca,
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.",
keywords = "Angiogenesis, Glioblastoma, Nonviral, Sleeping beauty, Transposon",
author = "Ohlfest, {John R.} and Demorest, {Zachary L.} and Yasuhiko Motooka and Isabelita Vengco and Seunguk Oh and Eleanor Chen and Scappaticci, {Frank A.} and Saplis, {Rachel J.} and Ekker, {Stephen C} and Low, {Walter C.} and Freese, {Andrew B.} and Largaespada, {David A.}",
year = "2005",
month = "11",
doi = "10.1016/j.ymthe.2005.07.689",
language = "English (US)",
volume = "12",
pages = "778--788",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - 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

AU - Ohlfest, John R.

AU - Demorest, Zachary L.

AU - Motooka, Yasuhiko

AU - Vengco, Isabelita

AU - Oh, Seunguk

AU - Chen, Eleanor

AU - Scappaticci, Frank A.

AU - Saplis, Rachel J.

AU - Ekker, Stephen C

AU - Low, Walter C.

AU - Freese, Andrew B.

AU - Largaespada, David A.

PY - 2005/11

Y1 - 2005/11

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Glioblastoma

KW - Nonviral

KW - Sleeping beauty

KW - Transposon

UR - http://www.scopus.com/inward/record.url?scp=27744497800&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27744497800&partnerID=8YFLogxK

U2 - 10.1016/j.ymthe.2005.07.689

DO - 10.1016/j.ymthe.2005.07.689

M3 - Article

C2 - 16150649

AN - SCOPUS:27744497800

VL - 12

SP - 778

EP - 788

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 5

ER -