Systemic administration of a conditionally replicating adenovirus, targeted to angiogenesis, reduced lung metastases burden in cotton rats

Clin Cancer Res. 2009 Mar 1;15(5):1664-73. doi: 10.1158/1078-0432.CCR-08-1670. Epub 2009 Feb 24.

Abstract

Purpose: Angiogenesis is an essential process for solid tumor development. To interfere with angiogenesis, AdPPE3x-E1, an adenovirus that is transcriptionally targeted to replicate in angiogenic endothelial cells, was constructed, by replacing the E1 promoter with the modified preproendothelin-1 promoter, PPE-1-3x, previously shown to induce specific transcription in angiogenic endothelial cells.

Experimental design: The specificity of AdPPE3x-E1 to endothelial cells was shown by quantitative PCR and immunostaining, and its antiangiogenic effect was evaluated in Matrigel models. The in vivo efficacy of AdPPE3x-E1 was also tested in a cotton rat lung metastases model.

Results: The replication rate of AdPPE3x-E1 in endothelial cells was similar to that of AdCMV-E1, a nonselective replicating adenovector, but the replication rate was reduced up to 60-fold in nonendothelial cells. Moreover, AdPPE3x-E1 reduced endothelial cell viability by 90% whereas nonendothelial cells were not affected. In in vitro and in vivo Matrigel models, endothelial cells infected with AdPPE3x-E1 did not develop capillary-like structures. The systemic administration of AdPPE3x-E1 reduced the lung metastases burden in a cotton rat model by 55%, compared with saline-treated rats, without significant evidence of toxicity. Quantitative PCR analysis showed that the viral copy number of AdPPE3x-E1 was increased 3-fold in the lung metastases but not in the liver, compared with a nonreplicating adenovector control.

Conclusions: We have shown here for the first time an antimetastatic effect induced by an angiogenesis-transcriptionally targeted adenovirus following systemic administration. Because adenovirus replication is more efficient in humans than in cotton rats, we assume a significant effect for AdPPE3x-E1 treatment in fighting human solid tumors and metastases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / physiology*
  • Adenovirus E1 Proteins / genetics
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cells, Cultured
  • Collagen / metabolism
  • DNA Replication
  • Drug Combinations
  • Endothelin-1 / genetics
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / virology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • Humans
  • Kidney / cytology
  • Kidney / metabolism
  • Kidney / virology
  • Laminin / metabolism
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy*
  • Lung Neoplasms / virology
  • Neovascularization, Pathologic
  • Promoter Regions, Genetic / genetics
  • Proteoglycans / metabolism
  • Rats
  • Sigmodontinae
  • Skin / cytology
  • Skin / metabolism
  • Skin / virology
  • Umbilical Veins / cytology
  • Virus Replication / physiology*

Substances

  • Adenovirus E1 Proteins
  • Angiogenesis Inhibitors
  • Drug Combinations
  • Endothelin-1
  • Laminin
  • Proteoglycans
  • matrigel
  • Collagen