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Tumor-specific intravenous gene delivery using oncolytic adenoviruses

Cancer Gene Therapy volume 12, pages 19–25 (2005)Cite this article

Abstract

In this report, we describe a vector system that specifically delivers transgene products to tumors following intravenous (i.v.) administration. The Escherichia coli cytosine deaminase (CD) gene was placed in the E3B region of the tumor-selective, replication-competent adenovirus ONYX-411, under the control of endogenous viral late gene regulatory elements. Thus, CD expression was directly coupled to the tumor-selective replication of the viral vector. In vitro, CD was expressed efficiently in various human cancer cell lines tested but not in cultured normal human cells, including human hepatocytes. Following i.v. administration into nude mice carrying human tumor xenografts, robust CD activity was detected only in tumors but not in liver or other normal tissues. Levels of CD activity in the tumors increased progressively following i.v. virus administration, correlating closely with virus replication in vivo. Subsequent administration of 5-fluorocytosine (5-FC) demonstrated a trend to improve the antitumor efficacy of these viruses in a mouse xenograft model, presumably due to the intratumoral conversion of 5-FC to the chemotherapeutic drug 5-fluorouracil. We show that the combination of a highly selective oncolytic virus, ONYX-411, with the strategic use of the viral E3B region for transgene insertion provides a powerful platform that allows for tumor-specific, persistent and robust transgene expression after i.v. administration. This technology provides an opportunity to enhance greatly both safety and efficacy of cancer gene therapy.

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Acknowledgements

We thank Drs Douglas Hanahan and Aleida Perez for critically reading the manuscript; Susan Collins and Elizabeth Sevilla for their help in preparing the manuscript.

Author information

Author notes

  1. Jinghui Zhan

    Present address: Amgen Inc., Thousand Oaks, CA, 91320, USA

  2. Yi Gao

    Present address: Cerus Corporation, Concord, CA, 94520, USA

  3. Wensheng Wang

    Present address: Berlex Inc., Richmond, CA, 94806, USA

  4. Annie Shen

    Present address: Chiron Corporation, Emeryville, CA, 94608, USA

  5. Amy Aspelund

    Present address: Medimmune Inc., Mountain View, CA, 94043, USA

  6. Sylvie Laquerre

    Present address: ViroPharma Inc., Exton, PA, 19341, USA

Authors and Affiliations

  1. Onyx Pharmaceuticals Inc., Richmond, California, 94806, USA

    Jinghui Zhan, Yi Gao, Wensheng Wang, Annie Shen, Amy Aspelund, Mandy Young, Sylvie Laquerre, Leonard Post & Yuqiao Shen

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  1. Jinghui Zhan
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Correspondence to Yuqiao Shen.

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Zhan, J., Gao, Y., Wang, W. et al. Tumor-specific intravenous gene delivery using oncolytic adenoviruses. Cancer Gene Ther 12, 19–25 (2005). https://doi.org/10.1038/sj.cgt.7700730

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