Eradication of primary murine fibrosarcomas and induction of systemic immunity by adenovirus-mediated interferon beta gene therapy.
We determined whether an adenoviral vector-mediated murine IFN-beta 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-beta, an adenoviral vector encoding murine IFN-beta driven by the human cytomegalovirus promoter, expressed high levels of steady-state IFN-beta mRNA and produced 500 or 7,000 units of IFN-beta activity/10(6) cells/24 h, respectively. Infection of tumor cells with 30 multiplicity of infection of AdCIFN-beta (but not control AdCLacZ vector) inhibited in vitro tumor cell proliferation by 40-45%. Intralesional injection of 5 x 10(8) plaque-forming units of AdCIFN-beta (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-beta 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-beta-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-beta gene therapy delivered by adenoviral vectors can be effective against fibrosarcomas.
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Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Fidler
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Dong
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D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology / Q000628:therapy*; D015316:Genetic Therapy; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology
D018809:Proliferating Cell Nuclear Antigen; D016899:Interferon-beta