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Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

Gene Therapy volume 14, pages 227–236 (2007)Cite this article

Abstract

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-α mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adβgal, Adβgal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

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Acknowledgements

This work was supported by a grant from the National Cancer Institute P50-58204 Specialized Program for Research Excellence (SPORE). Portions of this work were conducted in facilities provided by the Michael E DeBakey VA Medical Center.

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Authors and Affiliations

  1. Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

    T Fujita, T L Timme, K Tabata, K Naruishi, N Kusaka, M Watanabe, E Abdelfattah, C Ren, C Ren, G Yang, A Goltsov, H Wang & T C Thompson

  2. Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, USA

    T L Timme, M T Vlachaki, B S Teh & T C Thompson

  3. Department of Radiology, Baylor College of Medicine, Houston, TX, USA

    J X Zhu, B S Teh, E B Butler & T C Thompson

  4. The Methodist Hospital, Houston, TX, USA

    M T Vlachaki, B S Teh & E B Butler

  5. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    T C Thompson

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  1. T Fujita
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  2. T L Timme
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Correspondence to T C Thompson.

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Fujita, T., Timme, T., Tabata, K. et al. Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer. Gene Ther 14, 227–236 (2007). https://doi.org/10.1038/sj.gt.3302788

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