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Novel cancer antiangiotherapy using the VEGF promoter-targeted artificial zinc-finger protein and oncolytic adenovirus

Authors
 Yoon-A Kang  ;  Hyun-Chul Shin  ;  Ji Young Yoo  ;  Joo-Hang Kim  ;  Jin-Soo Kim  ;  Chae-Ok Yun 
Citation
 MOLECULAR THERAPY, Vol.16(6) : 1033-1040, 2008 
Journal Title
 MOLECULAR THERAPY 
ISSN
 1525-0016 
Issue Date
2008
MeSH
Adenoviridae/genetics* ; Angiogenesis Inhibitors/pharmacology* ; Animals ; Apoptosis ; Endothelium, Vascular/cytology ; Glioblastoma/therapy ; Humans ; Mice ; Neoplasm Transplantation ; Oncolytic Viruses/genetics* ; Promoter Regions, Genetic ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A/genetics* ; Vascular Endothelial Growth Factor A/metabolism ; Zinc Fingers*
Keywords
Adenoviridae/genetics* ; Angiogenesis Inhibitors/pharmacology* ; Animals ; Apoptosis ; Endothelium, Vascular/cytology ; Glioblastoma/therapy ; Humans ; Mice ; Neoplasm Transplantation ; Oncolytic Viruses/genetics* ; Promoter Regions, Genetic ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A/genetics* ; Vascular Endothelial Growth Factor A/metabolism ; Zinc Fingers*
Abstract
Inhibition of tumor angiogenesis through modulation of vascular endothelial growth factor (VEGF) and its signaling pathway has been clinically validated as a viable therapeutic modality in the treatment of cancer. The use of artificial transcription factors based on Cys2-His2 zinc-finger proteins (ZFPs) targeting the VEGF promoter offers a novel strategy for modulating VEGF levels in tumors. In order to demonstrate the utility of VEGF-targeted ZFPs as therapeutic agents, we generated adenoviruses (Ads) expressing VEGF promoter-targeted transcriptional repressor ZFP, F435-KOX. A replication-incompetent Ad expressing F435-KO X, namely, Ad-DeltaE1-KOX, significantly reduced VEGF expression and functionally led to inhibition of angiogenesis. In vivo, an oncolytic Ad expressing F435-KOX, namely, Ad-DeltaB7-KOX, elicited a pronounced antitumor effect against a human glioblastoma xenograft model, U87MG. Further, consistent with its expected mechanism of action, Ad-DeltaB7-KOX was shown to greatly reduce the level of VEGF and vessel density in tumor tissue and increase terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic cells in tumors. Survival rates were also significantly increased in Ad-DeltaB7-KOX-treated mice. Taken together, the findings from this study identify F435-KOX as a novel and potent ZFP transcription factor that can inhibit VEGF-A-mediated angiogenesis and offer a novel therapeutic modality in the treatment of cancer.
Full Text
http://www.nature.com/mt/journal/v16/n6/full/mt200863a.html
DOI
10.1038/mt.2008.63
Appears in Collections:
5. Research Institutes (연구소) > Institute for Cancer Research (암연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Yoon-A(강윤아)
Kim, Joo Hang(김주항)
Yoo, Ji Yeong(유지영)
Yun, Chae Ok(윤채옥)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/106902
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