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

Our plain-English summary of 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, by A. Kitamura, K. Matsushita, Y. Takiguchi, et al (Cancer Science, 2011).

The study

• Authors: A. Kitamura, K. Matsushita, Y. Takiguchi, H. Shimada, Y. Tada, M. Yamanaka, K. Hiroshima, M. Tagawa, T. Tomonaga, H. Matsubara, M. Inoue, M. Hasegawa, Y. Sato, D. Levens, K. Tatsumi, F. Nomura
• Journal: Cancer Science
• Published: 2011;102(7):1366-73
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2011 Japanese Cancer Association.

In plain English

This was a laboratory (preclinical) study in human cell lines and in a mouse model, not a study of people exposed to asbestos; asbestos was mentioned only as the background reason mesothelioma numbers are expected to rise. The authors built a fusion-gene-deleted, non-transmissible Sendai virus vector carrying the c-myc repressor FIR (SeV/dF/FIR) and compared it with the same vector carrying green fluorescent protein (SeV/dF/GFP) and with saline. They tested three human malignant pleural mesothelioma cell lines (MSTO-211H, H2452, H226) and a non-tumour immortalised mesothelial line (Met5A), and treated nude mice bearing 211H tumours in the pleural cavity, with or without cisplatin. The GFP-carrying vector transduced more than 90% of cells at a multiplicity of infection above 1000. The FIR vector reduced viability of all three mesothelioma lines dose-dependently and was less effective in Met5A, raised FIR, lowered c-Myc, and activated caspase-3 and caspase-9. With cisplatin in 211H the combination index was 0.72, indicating synergism. In mice, 1x10(8) CIU/body reduced tumour weight, while 1x10(7) CIU/body gave no significant tumour reduction compared with SeV/dF/GFP. The authors concluded the combination has therapeutic potential against mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: in vitro cell-line experiments plus an orthotopic xenograft mouse model of human malignant pleural mesothelioma
• Who was studied: Three human malignant pleural mesothelioma cell lines (MSTO-211H, H2452, H226) and a non-tumorigenic mesothelial line (Met5A), plus 8-week-old male BALB/c nu/nu mice injected intrathoracically with 1 x 10(6) 211H cells; work done at Chiba University, Japan (published 2011)
• Exposure: Treatment exposure, not asbestos: the FIR-encoding Sendai virus vector SeV/dF/FIR (10, 100, 1000 MOI in vitro; 1x10(8) or 1x10(7) CIU per body in mice), compared with SeV/dF/GFP and PBS, with or without cisplatin (0.12 mg/body intraperitoneally in mice)
• Main results:
  • Transduction with the GFP vector was dose-dependent, with more than 90% GFP-positive cells at MOI above 1000
  • All three mesothelioma lines were more efficiently killed by SeV/dF/FIR than by SeV/dF/GFP in a dose-dependent manner, but this was not the case for the immortalised non-tumour mesothelial line Met5A
  • ED50 values (MOI) for SeV/dF/FIR: 211H 472.1 ± 171.4; H2452 124.3 ± 19.9 (P = 0.026 vs 211H); H226 164.7 ± 13.5 (P = 0.037); the non-tumour mesothelial line Met5A 1.96 x 10(5) ± 2.27 x 10(5) (P = 0.274)
  • In all three mesothelioma lines the FIR vector increased FIR, decreased c-Myc and pro-forms of caspase-3 and caspase-9, and increased cleaved caspase-3 and caspase-9 compared with the GFP vector
  • In 211H cells the cisplatin IC50 was 2.22 ± 0.09 micrograms/mL and the combination index with SeV/dF/FIR was 0.72, which the authors read as moderate to slight synergism
  • In mice, SeV/dF/FIR at 1 x 10(8) CIU/body reduced tumour growth, with tumour weights measured on day 29 (n = 10)
  • At the lower dose of 1 x 10(7) CIU/body the FIR vector gave no significant tumour reduction compared with the GFP vector
  • The authors reported significant tumour reduction and improved survival rate for the combination of SeV/dF/FIR plus cisplatin in the animal model (survival compared by log-rank test, n = 9 per group for the combination)
  • Haematological values in the mice did not differ significantly between the three groups on day 29
  • The authors reported that haematological values and blood biochemistry in the mice showed no significant side-effects
• The authors' conclusion: The authors concluded that SeV/dF/FIR has therapeutic potential against human malignant pleural mesothelioma and that combination with cisplatin enhanced the antitumour effect in vitro and in vivo
• Limitations the authors state:
  • The authors said further experiments were needed before conclusions about the synergy with cisplatin could be applied clinically
  • The mechanism of the histological changes and of apoptosis induction in vivo was not established
  • The mechanism by which FIR might alter cisplatin sensitivity remained to be studied

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Synergistic Effect, Cisplatin, Pleural Mesothelioma, Apoptosis, Mesothelial Cells.

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