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Targeted endostatin-cytosine deaminase fusion gene therapy plus 5-fluorocytosine suppresses ovarian tumor growth

Oncogene volume 32, pages 1082–1090 (2013)Cite this article

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Abstract

There are currently no effective therapies for cancer patients with advanced ovarian cancer, therefore developing an efficient and safe strategy is urgent. To ensure cancer-specific targeting, efficient delivery, and efficacy, we developed an ovarian cancer-specific construct (Survivin-VISA-hEndoyCD) composed of the cancer specific promoter survivin in a transgene amplification vector (VISA; VP16-GAL4-WPRE integrated systemic amplifier) to express a secreted human endostatin-yeast cytosine deaminase fusion protein (hEndoyCD) for advanced ovarian cancer treatment. hEndoyCD contains an endostatin domain that has tumor-targeting ability for anti-angiogenesis and a cytosine deaminase domain that converts the prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic drug, 5-fluorouracil. Survivin-VISA-hEndoyCD was found to be highly specific, selectively express secreted hEndoyCD from ovarian cancer cells, and induce cancer-cell killing in vitro and in vivo in the presence of 5-FC without affecting normal cells. In addition, Survivin-VISA-hEndoyCD plus 5-FC showed strong synergistic effects in combination with cisplatin in ovarian cancer cell lines. Intraperitoneal (i.p.) treatment with Survivin-VISA-hEndoyCD coupled with liposome attenuated tumor growth and prolonged survival in mice bearing advanced ovarian tumors. Importantly, there was virtually no severe toxicity when hEndoyCD is expressed by Survivin-VISA plus 5-FC compared with CMV plus 5-FC. Thus, the current study demonstrates an effective cancer-targeted gene therapy that is worthy of development in clinical trials for treating advanced ovarian cancer.

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Acknowledgements

This work was supported by grants from National Science Council (NSC100-3112-B-039-003), Private University (NSC99-2314-B-039-029-MY3 to Y-PS and NSC99-2632-B to M-CH), Department of Health Cancer Research Center of Excellence (DOH99-TD-C-111-005), and The Sister Institution Fund of China Medical University and Hospital and The University of Texas MD Anderson Cancer Center.

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Authors and Affiliations

  1. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan

    Y-P Sher, C-M Chang & M-C Hung

  2. Division of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan

    C-Y Lin

  3. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    Y-P Sher & C-Y Lin

  4. Graduate Institute for Cancer Biology, China Medical University, Taichung, Taiwan

    M-C Hung

  5. Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan

    C-G Juo

  6. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan

    S-G Shiah

  7. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C-T Chen, J L Hsu, Z Han & M-C Hung

  8. Asia University, Taichung, Taiwan

    J L Hsu & M-C Hung

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  1. Y-P Sher
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Correspondence to M-C Hung.

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A patent application has been filed for EndoCD and the technology been licensed to a biotech company for development.

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Sher, YP., Chang, CM., Juo, CG. et al. Targeted endostatin-cytosine deaminase fusion gene therapy plus 5-fluorocytosine suppresses ovarian tumor growth. Oncogene 32, 1082–1090 (2013). https://doi.org/10.1038/onc.2012.134

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