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Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy

Cancer Gene Therapy volume 13, pages 676–685 (2006)Cite this article

Abstract

We have previously reported that adenoviral vector-mediated interferon (IFN)-β gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immune-competent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) of adenoviral vector encoding for mouse IFN-β (AdmIFN-β), but not AdE/1 (a control adenoviral vector), produced approximately 60 ng/105 cells/24 h of IFN-β. The tumorigenicity of AdmIFN-β-transduced cells was dramatically reduced in the prostates of C57BL/6 mice. A single intratumoral injection of 2 × 109 PFU (plaque-forming unit) of AdmIFN-β inhibited tumor growth by 70% and prolonged survival of tumor-bearing mice. Intriguingly, this AdmIFN-β therapy did not alter the growth of tumors in inducible nitric oxide synthase (iNOS)-null C57BL/6 mice. Immunohistochemical analysis revealed that treatment of tumors with AdmIFN-β in wild-type C57BL/6 mice led to increased iNOS expression, decreased microvessel density, decreased cell proliferation, and increased apoptosis. Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-β therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-β1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-β gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-β antitumoral effects in vivo.

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Acknowledgements

We thank Dr Robert Franco (University of Cincinnati College of Medicine) for critical reading of this manuscript, Dr Corazon D Bucana (University of Texas MD Anderson Cancer Center) for technical assistance with immunohistochemical staining. This work is supported in part by funds from The University of Cincinnati College of Medicine Cancer Center Start-up funds (to ZD) and RSG-98-332-02-CCE from the American Cancer Society (to ZD).

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  1. M V Olson and J Lee: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M V Olson

  2. Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    J Lee, A Wang & Z Dong

  3. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    F Zhang

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  1. M V Olson
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Correspondence to Z Dong.

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Olson, M., Lee, J., Zhang, F. et al. Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy. Cancer Gene Ther 13, 676–685 (2006). https://doi.org/10.1038/sj.cgt.7700941

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