1. Systemic IFN-β gene therapy results in long-term survival in mice with established colorectal liver metastases
- Author
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Eugene Choi, Lee Ellis, David J. Maron, James Barsoum, Xiao Qin, Francis R. Spitz, Kathleen J. Propert, Hanqin Lei, Stephen Fawell, A. David Moscioni, Wenbiao Liu, Hiroomi Tada, Alan R. Davis, Douglas L. Fraker, John Tazelaar, James M. Wilson, and Qing Xie
- Subjects
DNA, Complementary ,Colorectal cancer ,Recombinant Fusion Proteins ,Genetic enhancement ,Genetic Vectors ,Cytomegalovirus ,Mice, Nude ,Apoptosis ,Mice, SCID ,Disease ,Adenocarcinoma ,Mouse model of colorectal and intestinal cancer ,medicine.disease_cause ,Article ,Adenoviridae ,Viral vector ,Mice ,Nude mouse ,Genes, Synthetic ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Promoter Regions, Genetic ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,biology ,business.industry ,Macrophages ,Liver Neoplasms ,Genetic Therapy ,Interferon-beta ,General Medicine ,medicine.disease ,biology.organism_classification ,Xenograft Model Antitumor Assays ,Killer Cells, Natural ,Injections, Intravenous ,Immunology ,Hepatocytes ,Cancer research ,Female ,Colorectal Neoplasms ,business ,Injections, Intraperitoneal ,Neoplasm Transplantation - 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.
- Published
- 2001