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Human malignant pleural mesothelioma (HMPM) is highly resistant to conventional therapy, and therefore novel therapies are required. We previously reported that overexpression of the FUSE-binding protein-interacting repressor (FIR), a c-myc transcriptional repressor, induces apoptosis via c-Myc suppression, and is thus a suitable cancer therapy. In the current preclinical trial, a fusion gene deleted non-transmissible Sendai virus vector encoding FIR (SeV/ΔF/FIR) was prepared and its cytotoxic activity against an orthotopic xenograft model of HMPM, in combination with cisplatin, was assessed. SeV/ΔF/FIR and a fusion gene deleted non-transmissible Sendai virus vector encoding green fluorescent protein (SeV/ΔF/GFP) were prepared. The transduction efficiency of these agents in terms of dose-dependent cytotoxicity and/or apoptosis induction was then assessed in a few HMPM cells. Combination therapy with SeV/ΔF/FIR plus cisplatin was evaluated in vitro and in a mouse model. SeV/ΔF/FIR significantly reduced cell viability in three HMPM cell lines but was less effective in non-tumor immortalized mesothelial cells. SeV/ΔF/FIR cytotoxicity was partly due to apoptosis induction via c-Myc suppression. In addition, SeV/ΔF/FIR showed synergistic antitumor effects in combination with cisplatin, as was revealed by isobologram analysis in MSTO-211H. Moreover, combination therapy with SeV/ΔF/FIR plus cisplatin demonstrated significant tumor reduction and improvement in survival rate in an animal model. Combination therapy with SeV/ΔF/FIR plus cisplatin has therapeutic potential against HMPM. SeV/ΔF/FIR plus cisplatin will be an attractive modality against HMPM in the future. (Cancer Sci 2011; 102: 1366–1373)