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Antitumor Activity of IFN- in Murine Tumor Models¹

Atsuko Sato^*,, Mamitaro Ohtsuki, Megumi Hata^*, Eiji Kobayashi^* and Takashi Murakami^2,*

^* Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Shimotsuke, Tochigi, Japan; and Department of Dermatology, Jichi Medical School, Shimotsuke, Tochigi, Japan

IFN- 1, - 2 and - 3 have been discovered as the latest members of the class II cytokine family and shown to possess antiviral activity. Murine B16 melanoma and Colon26 cancer cells were transduced with mouse IFN- to determine whether IFN- possesses antitumor activity. Overexpression of IFN- induced cell surface MHC class I expression and Fas/CD95 Ag, induced significant caspase-3/7 activity, and increased p21^Waf1/Cip1 and dephosphorylated Rb (Ser⁷⁸⁰) in B16 cells in vitro. IFN- expression in tumor cell lines markedly inhibited s.c. and metastatic tumor formation in vivo compared with mock transfections (p < 0.05). Moreover, IFN- expression induced lymphocytic infiltrates, and an Ab-mediated immune cell depletion assay showed that NK cells were critical to IFN--mediated tumor growth inhibition. Hydrodynamic injection of IFN- cDNA successfully targeted liver metastatic foci of Colon26 cells, and moderately decreased the mortality of mice with tumors. IFN- overexpression in the liver increased NK/NKT cells and enhanced their tumor-killing activity, and suggested the activation of innate immune responses. Thus, IFN- induced both tumor apoptosis and NK cell-mediated immunological tumor destruction through innate immune responses. These findings suggested that local delivery of IFN- might prove a useful adjunctive strategy in the clinical treatment of human malignancies.

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