Transcription-controlled gene therapy against tumor angiogenesis

J Clin Invest. 2004 Apr;113(7):1017-24. doi: 10.1172/JCI20007.


A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell-specific apoptosis, using adenoviral vector-mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-alpha. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1-based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Apoptosis / physiology
  • Cattle
  • Endothelial Cells / metabolism
  • Genetic Therapy*
  • Genetic Vectors
  • Humans
  • Neoplasms / therapy*
  • Neovascularization, Pathologic / therapy*
  • Transcription, Genetic*
  • Tumor Necrosis Factor-alpha / metabolism
  • fas Receptor / genetics*
  • fas Receptor / metabolism


  • Tumor Necrosis Factor-alpha
  • fas Receptor