Tissue-specific Gene Therapy Directed to Tumor Angiogenesis

Gene Ther. 2001 Jun;8(11):819-27. doi: 10.1038/sj.gt.3301472.

Abstract

Gene therapy directed specifically to the vascular wall, particularly to angiogenic endothelial cells is a prerequisite in vascular disease treatment. Angiogenesis is a major feature in many pathological conditions including wound healing, solid tumors, developing metastases, ischemic heart diseases and diabetic retinopathy. In the present study we developed a tissue-specific gene therapy to the angiogenic blood vessels of tumor metastasis using an adeno-based vector containing the murine preproendothelin-1 (PPE-1) promoter. Genes activated by the PPE-1 promoter were highly expressed in bovine aortic endothelial cells in vitro. Systemic injection of the adenoviral vectors AdPPE-1-luciferase and AdCMV-luciferase to normal C57BL/6 mice, resulted in higher activity of PPE-1 promoter compared with CMV promoter in the aorta and vascularized tissues such as heart, kidney, lung and pancreas. Systemic administration of the adenoviral vector, in mice bearing Lewis lung carcinoma, resulted in high and specific activity of PPE-1 in the new vasculature of primary tumors and lung metastasis. Cellular distribution of the delivered gene revealed highest expression of GFP in angiogenic endothelial cells of the metastasis. We expect that this approach of 'vascular-directed' gene therapy will be applicable to both vascular diseases and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Analysis of Variance
  • Animals
  • Aorta
  • Carcinoma, Lewis Lung / blood supply
  • Carcinoma, Lewis Lung / secondary*
  • Carcinoma, Lewis Lung / therapy
  • Cattle
  • Cells, Cultured
  • Endothelin-1 / genetics
  • Endothelins / genetics*
  • Endothelium, Vascular / metabolism*
  • Gene Expression
  • Gene Targeting / methods
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Green Fluorescent Proteins
  • Liver / metabolism
  • Luminescent Proteins / genetics
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / secondary*
  • Lung Neoplasms / therapy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Microscopy, Phase-Contrast
  • Neovascularization, Pathologic*
  • Promoter Regions, Genetic
  • Protein Precursors / genetics*
  • Statistics, Nonparametric

Substances

  • Endothelin-1
  • Endothelins
  • Luminescent Proteins
  • Protein Precursors
  • Green Fluorescent Proteins