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Original Paper

Specific Induction of Tumor Neovasculature Death by Modified Murine PPE-1 Promoter Armed with HSV-TK

Varda-Bloom N.a · Hodish I.a · Shaish A.a · Greenberger S.a · Tal R.a · Feder B.e · Roitelman J.b · Breitbart E.a · Bangio L.a · Barshack I.a · Pfeffer R.d · Harats D.a

Author affiliations

aVascular Biogenics Ltd., Or Yehuda, bThe Bert W. Strassburger Lipid Center, cInstitute of Pathology, dInstitute of Oncology, eGeriatrics Department, Sheba Medical Center, Tel Hashomer, and fSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Corresponding Author

Dror Harats, MD

Vascular Biogenics Ltd., 6 Jonathan Netanyahu

IL–60376 Or Yehuda (Israel)

Tel. +972 3 634 6450, Fax +972 3 634 1233

E-Mail dror@vbl.co.il

Related Articles for ""

Pathobiology 2008;75:346–355

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Abstract

Background: One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers. Objectives: (1) To enhance the selectivity of a murine preproendothelin-1 (PPE-1) promoter in tumor angiogenesis by using a positive endothelial transcription-binding element. (2) To test the specificity and efficiency of the modified PPE-1 promoter [PPE-1(3X)] in vitro and in vivo by using reporter genes, and the therapeutic gene herpes simplex virus-thymidine kinase (HSV-TK) in a mouse model of Lewis lung carcinoma (LLC). Results: The modified PPE-1 promoter specifically induced expression in the tumor angiogenic vascular bed with a 35-fold higher expression compared to the normal vasculare bed of the lung. Thus, when the HSV-TK gene controlled by the modified PPE-1 promoter was used systemically, it induced tumor-specific necrosis, apoptosis and mononuclear infiltrates, leading to massive destruction of the neovasculature of the pulmonary metastasis, which suppressed metastasis development. Conclusions: These results show that an adenoviral vector armed with HSV-TK controlled by the endothelial-selective murine PPE-1(3X) promoter is efficient and safe to target tumor neovasculature.

© 2008 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: March 05, 2007
Accepted: August 07, 2008
Published online: December 15, 2008
Issue release date: December 2008

Number of Print Pages: 10
Number of Figures: 6
Number of Tables: 0

ISSN: 1015-2008 (Print)
eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


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