Specific Induction of Tumor Neovasculature Death by Modified Murine PPE-1 Promoter Armed with HSV-TKVarda-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
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
Dror Harats, MD
Vascular Biogenics Ltd., 6 Jonathan Netanyahu
IL–60376 Or Yehuda (Israel)
Tel. +972 3 634 6450, Fax +972 3 634 1233
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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
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