Abstract
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
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / secondary*
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Adenocarcinoma / therapy
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Adenoviridae / genetics*
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Animals
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Apoptosis
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Colorectal Neoplasms / pathology*
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Cytomegalovirus / genetics
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DNA, Complementary / administration & dosage
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DNA, Complementary / genetics
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DNA, Complementary / therapeutic use*
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DNA, Complementary / toxicity
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Female
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Genes, Synthetic
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Genetic Therapy*
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Genetic Vectors / administration & dosage
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Genetic Vectors / genetics
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Genetic Vectors / therapeutic use*
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Genetic Vectors / toxicity
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Hepatocytes / metabolism
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Humans
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Injections, Intraperitoneal
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Injections, Intravenous
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Interferon-beta / administration & dosage
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Interferon-beta / genetics
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Interferon-beta / therapeutic use*
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Interferon-beta / toxicity
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Liver Neoplasms / drug therapy
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Liver Neoplasms / secondary*
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Liver Neoplasms / therapy
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Macrophages / drug effects
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Macrophages / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mice, SCID
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Neoplasm Transplantation
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / therapy
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Promoter Regions, Genetic
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / physiology
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Recombinant Fusion Proteins / therapeutic use
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Recombinant Fusion Proteins / toxicity
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Tumor Cells, Cultured / transplantation
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Xenograft Model Antitumor Assays
Substances
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DNA, Complementary
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Recombinant Fusion Proteins
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Interferon-beta