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Eradication of Primary Murine Fibrosarcomas and Induction of Systemic Immunity by Adenovirus-mediated Interferon Gene Therapy¹

Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

We determined whether an adenoviral vector-mediated murine IFN- gene therapy could eradicate established s.c. tumors produced by murine UV-2237m fibrosarcoma cells. The tumor cells were highly susceptible to infection by adenoviral vectors. Cells infected with 10 or 100 multiplicity of infection of AdCIFN-, an adenoviral vector encoding murine IFN- driven by the human cytomegalovirus promoter, expressed high levels of steady-state IFN- mRNA and produced 500 or 7,000 units of IFN- activity/10⁶ cells/24 h, respectively. Infection of tumor cells with 30 multiplicity of infection of AdCIFN- (but not control AdCLacZ vector) inhibited in vitro tumor cell proliferation by 40–45%.

Intralesional injection of 5 x 10⁸ plaque-forming units of AdCIFN- (but not AdLacZ) eradicated established s.c. fibrosarcomas in syngeneic mice but not fibrosarcomas in nude mice. Mice cured of the disease developed systemic immunity against rechallenge with UV-2237m cells but not against another syngeneic tumor, the K-1735 M2 melanoma. Immunohistochemical analysis revealed that tumors injected with AdCIFN- contained more macrophages and CD4⁺ and CD8⁺ cells than did tumors injected with AdCLacZ or saline. Most cells in the PBS- and AdCLacZ-treated tumors stained positive for proliferating cell nuclear antigen, and few cells stained for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling. In sharp contrast, AdCIFN--treated tumors contained few proliferating cell nuclear antigen-positive cells and many terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-positive cells. Taken together, our data demonstrate that IFN- gene therapy delivered by adenoviral vectors can be effective against fibrosarcomas.

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