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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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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


  1. Binley K, Iqball S, Kingsman A, Kingsman S, Naylor S: An adenoviral vector regulated by hypoxia for the treatment of ischemic disease and cancer. Gene Ther 1999;6:1721–1727.
  2. Graulich W, Nettelbeck DM, Ficher D, Kissel T, Muller R: Cell type specificity of the human endoglin promoter. Gene 1999;227:55–62.
  3. Jaggar RT, Chan HY, Harris AL, Bicknell R: Endothelial cell specific expression of tumor necrosis factor alpha from KDR or E-selectin promoters following retroviral delivery. Hum Gene Ther 1997;8:2239–2247.
  4. Jäger U, Zhao Y, Porter CD: Endothelial cell-specific transcriptional targeting from a hybrid long terminal repeat retrovirus vector containing human prepro-endothelin-1 promoter sequences. J Virol 1999;73:9702–9709.
  5. Modlich U, Pugh CW, Bicknell R: Increasing endothelial cell specific expression by the use of heterologous hypoxic and cytokine-inducible enhancers. Gene Ther 2000;7:896–902.
  6. Nettelbeck DM, Jerome V, Muller R: Gene therapy: designer promoters for tumor targeting. Trends Genet 2000;16:174–181.
  7. Reynolds PN, Nicklin SA, Kaliberova L, Boatman BG, Grizzle WE, Balyasnikova K, Baker AH, Danilov SM, Curiel DT: Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat Biotech 2001;19:838–842.
  8. Ribault S, Nueville P, Mechine-Neuville A, Auge F, Parlakian A, Gabbiani G, Paulin D, Calenda Y: Chimeric smooth muscle specific enhancer/promoters. Valuable tools for adenovirus mediated cardiovascular gene therapy. Circ Res 2001;88:468–475.
  9. Ruan H, Su H, Hu L, Lamborn KR, Kan YW, Deen DF: A hypoxia regulated adeno-associated virus vector for cancer specific gene therapy. Neoplasia 2001;3:255–263.
  10. Shibata T, Giaccia AJ, Brown JM: Development of a hypoxia responsive vector for tumor specific gene therapy. Gene Ther 2000;7:493–498.
  11. Weeratna RD, Wu T, Efler SM, Zhang L, Davis HL: Designing gene therapy vectors: avoiding immune responses by using tissue-specific promoters. Gene Ther 2001;8:1872–1878.
  12. Mercier S, Gahery-Segard H, Monteil M, Lengagne R, Guillet JR, Eliot M, Denesvre C: Distinct roles of adenovirus vector-transduced dendritic cells, myoblasts, and endothelial cells in mediating an immune response against transgene product. J Virol 2002;76:2899–2911.
  13. Sauter BV, Martinet O, Zhang WJ, Mandeli J, Woo SL: Adenovirus-mediated gene transfer of endostatin in vivo results in high levels of transgene expression and inhibition of tumor growth and metastases. Proc Natl Acad Sci USA 2000;97:4802–4807.
  14. Chen CT, Lin J, Li Q,, Phipps SS, Jkubczak JL, Stewart DA, Skripchenko Y, Forry-Schaudies S, Wood J, Schnell C, Hallenbeck PL: Antiangiogenic gene therapy for cancer via systemic administration of adenoviral vectors expressing secretable endostatin. Hum Gen Ther 2000;11:1983–1996.
  15. Feldman AL, Restifo NP, Alexander HR, Barlett DL, Hwu P, Seth P, Libutti SK: Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice. Cancer Res 2000;60:1503–1506.
  16. Varda-Bloom N, Shaish A, Gonen A, Levanon K, Greenberger S, Ferber S, Levkovitz H, Castel D, Goldberg I, Afek A, Kopolovitc Y, Harats D: Tissue-specific gene therapy directed to tumor angiogenesis. Gene Ther 2001;8:819–827.
  17. Bu X, Quertermous T: Identification of endothelin-1 cell specific regulatory region in the murine endothelin-1 gene. J Biol Chem 1997;272:32613–32622.
  18. van Dillen IJ, et al: Influence of the bystander effect on HSV-tk/GCV gene therapy. A review. Curr Gene Ther 2002;2:307–322.
  19. Mavria G, Harrington KJ, Marshall CJ, Porter CD: In-vivo efficacy of HSV-TK transcriptionaly targeted to the tumor vasculature is augmented by combination with cytotoxic chemotherapy. J Gene Med 2005;7:263–275.
  20. Seijffers R, Ben David O, Cohen Y, Karasik A, Berezin M, Newgard CB, Ferber S: Increase in PDX-1 levels suppresses insulin gene expression in RIN 1046–38 cells. Endocrinology 1999;140:3311–3317.
  21. Jaffe EA, Nachman RL, Becker CG, Minick CR: Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 1973;52:2745–2756.
  22. Harats D, Kurihara H, Belloni P, Oakley H, Ziobe A, Ackley D, Cain G, Kurihara Y, Lawn R, Sigal E: Targeting gene expression to the vascular wall in transgenic mice using the murine preproendothelin-1 promoter. J Clin Invest 1995;95:1335–1344.
  23. Ellis LM, Staley CA, Liu W, Fleming RY, Parikh NU, Bucana CD, Gallick GE: Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem 1998;273:1052–1057.
  24. Nicklin SA, et al: Analysis of cell specific promoters for viral gene therapy targeted at the vascular endothelium. Hypertension 2001;38:65–70.
  25. Song W, Sun Q, Dong Z, Spencer DM, Numez G, Nor JE: Antiangiogenic gene therapy: disruption of neovascular networks mediated by inducible caspase-9 delivered with transcriptionally targeted adenoviral vector. Gene Ther 2005;12:320–329.
  26. Dancer A, Julian S, Bouillot S, Pointu H, Vernet M, Huber P: Expression of thymidine kinase driven by an endothelial specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice. Gene Ther 2003;10:1170–1178.
  27. Walton T, Wang JL, Ribas A, Barsky SH, Economou J, Ngnyen M: Endothelium-specific expression of an E-selectin promoter recombinant adenoviral vector. Anticancer Res 1998;18:1357–1360.
  28. Greenberger S, Shaish A, Varda-Bloom N, Levanon K, Breitbart E, Goldberg I, Barshack I, Hodish I, Yaccov N, Bangio L, Goncharov T, Wallach D, Harats D: Transcription controlled gene therapy against tumor angiogenesis. J Clin Invest 2004;113:1017–1024.
  29. Levanon K, Varda-Bloom N, Greenberg S, Barshack I, Goldberg I, Orenstein A, Breitbart E, Shaish A, Harats D: Vascular wall maturation and prolonged angiogenic effect by endothelial-specific platelet-derived growth factor expression. Pathobiology 2006;73:149–158.

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: https://www.karger.com/PAT

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