Systemic IFN-beta gene therapy results in long-term survival in mice with established colorectal liver metastases

J Clin Invest. 2001 Jul;108(1):83-95. doi: 10.1172/JCI9841.


Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-beta (hIFN-beta) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-beta in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-beta gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-beta (mIFN-beta) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-beta in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.

Publication types

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

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / secondary*
  • Adenocarcinoma / therapy
  • Adenoviridae / genetics*
  • Animals
  • Apoptosis
  • Colorectal Neoplasms / pathology*
  • Cytomegalovirus / genetics
  • DNA, Complementary / administration & dosage
  • DNA, Complementary / genetics
  • DNA, Complementary / therapeutic use*
  • DNA, Complementary / toxicity
  • Female
  • Genes, Synthetic
  • Genetic Therapy*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Genetic Vectors / therapeutic use*
  • Genetic Vectors / toxicity
  • Hepatocytes / metabolism
  • Humans
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Interferon-beta / administration & dosage
  • Interferon-beta / genetics
  • Interferon-beta / therapeutic use*
  • Interferon-beta / toxicity
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / secondary*
  • Liver Neoplasms / therapy
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / therapy
  • Promoter Regions, Genetic
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / physiology
  • Recombinant Fusion Proteins / therapeutic use
  • Recombinant Fusion Proteins / toxicity
  • Tumor Cells, Cultured / transplantation
  • Xenograft Model Antitumor Assays


  • DNA, Complementary
  • Recombinant Fusion Proteins
  • Interferon-beta