387 445

Cited 20 times in

A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFbeta signaling for breast cancer therapy.

Authors
 Zebin Hu  ;  John S. Robbins  ;  Amanda Pister  ;  M. Behzad Zafar  ;  Zhen-Wei Zhang  ;  Janhavi Gupta  ;  K. Jessica Lee  ;  Kam Neuman  ;  Chae-Ok Yun  ;  Theresa Guise  ;  Prem Seth 
Citation
 CANCER GENE THERAPY, Vol.17(4) : 235-243, 2010 
Journal Title
CANCER GENE THERAPY
ISSN
 0929-1903 
Issue Date
2010
MeSH
Adenoviridae/physiology* ; Adenoviridae Infections/genetics ; Adenoviridae Infections/therapy ; Adenoviridae Infections/virology ; Animals ; Blotting, Western ; Breast Neoplasms/genetics ; Breast Neoplasms/therapy* ; Breast Neoplasms/virology ; Cell Line, Tumor ; Cytopathogenic Effect, Viral ; Enzyme-Linked Immunosorbent Assay ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Vectors ; Humans ; Immunoglobulin Fc Fragments/genetics ; Mice ; Mice, Nude ; Oncolytic Virotherapy* ; Phosphorylation ; Promoter Regions, Genetic/genetics* ; Protein-Serine-Threonine Kinases/genetics ; Receptors, Transforming Growth Factor beta/genetics ; Signal Transduction ; Smad Proteins/metabolism ; Telomerase/genetics* ; Transforming Growth Factor beta/antagonists & inhibitors* ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Virus Replication* ; Xenograft Model Antitumor Assays
Abstract
We were interested in developing oncolytic adenoviral vectors that can be administered systemically for the treatment of breast cancer. To restrict viral replication in breast tumor cells, we constructed mhTERTAd.sTbetaRFc, a 01/07-based adenoviral vector expressing the soluble form of transforming growth factor-beta (TGFbeta) receptor II fused with the human Fc IgG1 (sTGFbetaRIIFc) gene, in which viral replication is under the control of a modified human telomerase reverse transcriptase (mhTERT) promoter. In addition, mhTERTAd.sTbetaRFc-mediated sTGFbetaRIIFc production targets the TGFbeta pathway known to contribute to the tumor progression of breast cancer metastasis. We chose to use the mhTERT promoter because it was found to be relatively more active (approximately 20 times) in breast cancer cells compared with normal human cells. We showed that infection of MDA-MB-231 and MCF-7 breast cancer cells for 48 h with mhTERTAd.sTbetaRFc produced high levels of sTGFbetaRIIFc (greater than 1 microg ml(-1)) in the medium. Breast cancer cells produced nearly a 6000-fold increase in viral titers during the 48 h infection period. However, mhTERTAd.sTbetaRFc replication was attenuated in normal cells. Infection of breast cancer cells with a replication-deficient virus Ad(E1(-)).sTbetaRFc also produced high levels of sTGFbetaRIIFc, but under these conditions, no detectable viral replication was observed. Adenoviral-mediated production of sTGFbetaRIIFc was shown to bind with TGFbeta-1, and to abolish the effects of TGFbeta-1 on downstream SMAD-3 phosphorylation. The administration of mhTERTAd.sTbetaRFc intravenously into MDA-MB-231 human xenograft-bearing mice resulted in a significant inhibition of tumor growth and production of sTGFbetaRIIFc in the blood. Conversely, intravenous injection of Ad(E1(-)).sTbetaRFc did not show a significant inhibition of tumor growth, but resulted in sTGFbetaRIIFc in the blood, suggesting that viral replication along with sTGFbetaRIIFc protein production is critical in inducing the inhibition of tumor growth. These results warrant future investigation of mhTERTAd.sTbetaRFc as an antitumor agent in vivo.
Files in This Item:
T201004893.pdf Download
DOI
10.1038/cgt.2009.72
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Yun, Chae Ok(윤채옥)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/102775
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links