Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer

Takefumi Satoh, Terry L. Timme, Takashi Saika, Shin Ebara, Guang Yang, Jianxiang Wang, Chengzhen Ren, Nobuyuki Kusaka, Vladimir Mouraviev, Timothy C. Thompson

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Abstract

We previously identified the mouse RTVP-1 (mRTVP-1; related to testes-specific, vespid, and pathogenesis proteins) gene as a direct target of p53 with proapoptotic activities in various cancer cell lines, including prostate cancer. To test the therapeutic potential of mRTVP-1 we constructed an adenoviral vector capable of efficient transduction and expression of mRTVP-1 (AdmRTVP-1) and used this vector in an orthotopic, metastatic mouse model of prostate cancer. A single intratumoral administration of AdmRTVP-1 gene therapy significantly reduced primary tumor wet weight compared with control Adβgal-injected tumors at two time points after injection with two different vector doses (p ≤ 0.01 at 7 and 14 days). Spontaneous metastasis to lung was also significantly reduced (p ≤ 0.02). Evaluation of treated tumors revealed increased apoptosis and lower microvessel density counts. In a rat aortic ring sprouting assay, AdmRTVP-1 inhibited endothelial cell sprouting compared with Adβgal, confirming its antiangiogenic activity. These therapeutic activities were associated with a significant increase in survival from 22.9 to 26.8 days (p = 0.003) in this aggressive model of prostate cancer. Interestingly, there were significant increases in the infiltration of tumor-associated macrophages, dendritic cells, and CD8+ T cells, which persisted at 14 days posttreatment in the AdmRTVP-1-treated tumors compared with Adβgal control-treated tumors. In addition, significantly increased natural killer and cytotoxic T lymphocyte activities were demonstrated in the mice with AdmRTVP-1-treated tumors. The unique therapeutic properties of AdmRTVP-1 gene therapy demonstrated in this study provide new opportunities for gene and immunotherapy of prostate cancer and potentially other malignancies.

Original languageEnglish
Pages (from-to)91-101
Number of pages11
JournalHuman Gene Therapy
Volume14
Issue number2
DOIs
Publication statusPublished - Jan 1 2003

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Satoh, T., Timme, T. L., Saika, T., Ebara, S., Yang, G., Wang, J., Ren, C., Kusaka, N., Mouraviev, V., & Thompson, T. C. (2003). Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer. Human Gene Therapy, 14(2), 91-101. https://doi.org/10.1089/104303403321070793