Gene therapy with recombinant adenovirus encoding endostatin encapsulated in cationic liposome in coxsackievirus and adenovirus receptor-deficient colon carcinoma murine models

Hum Gene Ther. 2011 Sep;22(9):1061-9. doi: 10.1089/hum.2011.014. Epub 2011 Jul 25.

Abstract

Adenovirus (Ad)-based antiangiogenesis gene therapy is a promising approach for cancer treatment. Downregulation or loss of coxsackievirus and adenovirus receptor (CAR) is often detected in various human cancers, which hampers adenoviral gene therapy approaches. Cationic liposome-complexed adenoviral vectors have been proven useful in CAR-deficient cells to enhance therapeutic gene transfer in vivo. Here, we investigated the antitumor effects of recombinant adenovirus encoding endostatin (Ad-hE) encapsulated in cationic liposome (Ad-hE/Lipo) on CAR-deficient CT26 colon carcinoma murine models. In vitro, Ad-hE/Lipo enhanced adenovirus transfection in CAR-deficient cells (CT26), and endostatin gene expression was measured by both qualitative and quantitative detection. In addition, an antibody neutralizing assay indicated that neutralizing serum inhibited naked adenovirus 5 (Ad5) at rather higher dilution than the complexes of Ad5 and cationic liposomes (Ad5-CL), which demonstrated that Ad5-CL was more capable of protecting Ad5 from neutralization. In vivo, Ad-hE/Lipo treatment in the murine CT26 tumor model by intratumoral injection resulted in marked suppression of tumor growth and prolonged survival time, which was associated with a decreased number of microvessels and increased apoptosis of tumor cells. In conclusion, recombinant endostatin adenovirus encapsulated with cationic liposome effectively inhibited CAR-deficient tumor growth through an antiangiogenic mechanism in murine models without marked toxicity, thus showing a feasible strategy for clinical applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy*
  • Adenoviridae / genetics*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy*
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Disease Models, Animal
  • Endostatins / genetics*
  • Endostatins / metabolism
  • Female
  • Gene Expression Regulation
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage*
  • Genetic Vectors / toxicity
  • HEK293 Cells
  • Humans
  • Liposomes
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / genetics
  • Receptors, Virus / deficiency
  • Transduction, Genetic
  • Tumor Burden / drug effects
  • Tumor Burden / genetics

Substances

  • CLMP protein, human
  • CLMP protein, mouse
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Endostatins
  • Liposomes
  • Receptors, Virus