title: Specific induction of tumor neovasculature death by modified murine PPE-1 promoter armed with HSV-TK.
abstract: BACKGROUND
  One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers.
  
  
  OBJECTIVE
  (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.
authors.affiliation: Vascular Biogenics Ltd., Or Yehuda, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Varda-Bloom
authors.forename: I
authors.initials: I
authors.lastname: Hodish
authors.forename: A
authors.initials: A
authors.lastname: Shaish
authors.forename: S
authors.initials: S
authors.lastname: Greenberger
authors.forename: R
authors.initials: R
authors.lastname: Tal
authors.forename: B
authors.initials: B
authors.lastname: Feder
authors.forename: J
authors.initials: J
authors.lastname: Roitelman
authors.forename: E
authors.initials: E
authors.lastname: Breitbart
authors.forename: L
authors.initials: L
authors.lastname: Bangio
authors.forename: I
authors.initials: I
authors.lastname: Barshack
authors.forename: R
authors.initials: R
authors.lastname: Pfeffer
authors.forename: D
authors.initials: D
authors.lastname: Harats
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000628:therapy*; D019332:Endothelin-1 / Q000235:genetics*; D004730:Endothelium, Vascular / Q000378:metabolism; D005814:Genes, Viral / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008168:Lung / Q000098:blood supply; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000628:therapy*; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D013937:Thymidine Kinase