title: Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma.
abstract: 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.
authors: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Atsushi
authors: A
authors: Kitamura
authors: Kazuyuki
authors: K
authors: Matsushita
authors: Yuichi
authors: Y
authors: Takiguchi
authors: Hideaki
authors: H
authors: Shimada
authors: Yuji
authors: Y
authors: Tada
authors: Makako
authors: M
authors: Yamanaka
authors: Kenzo
authors: K
authors: Hiroshima
authors: Masatoshi
authors: M
authors: Tagawa
authors: Takeshi
authors: T
authors: Tomonaga
authors: Hisahiro
authors: H
authors: Matsubara
authors: Makoto
authors: M
authors: Inoue
authors: Mamoru
authors: M
authors: Hasegawa
authors: Yasunori
authors: Y
authors: Sato
authors: David
authors: D
authors: Levens
authors: Koichiro
authors: K
authors: Tatsumi
authors: Fumio
authors: F
authors: Nomura
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D004268:DNA-Binding Proteins; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010997:Pleural Neoplasms / Q000473:pathology / Q000628:therapy*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D029082:Sendai virus / Q000235:genetics*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C410595:poly-U binding splicing factor 60KDa; D002945:Cisplatin