Efficient infection of tumor endothelial cells by a capsid-modified adenovirus

Gene Ther. 2006 Jan;13(1):52-9. doi: 10.1038/sj.gt.3302598.

Abstract

Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/35 may be useful in anticancer strategies targeting tumor endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviruses, Human / genetics*
  • Animals
  • Biomarkers / analysis
  • Capsid Proteins / genetics*
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / therapy
  • Endothelial Cells / virology*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Humans
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / therapy
  • Models, Animal
  • Neovascularization, Pathologic / therapy*
  • Neovascularization, Pathologic / virology
  • Platelet Endothelial Cell Adhesion Molecule-1 / analysis
  • Rats
  • Transduction, Genetic / methods*
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor Receptor-2 / analysis

Substances

  • Biomarkers
  • Capsid Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor Receptor-2