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Utility of TK/GCV in the context of highly effective oncolysis mediated by a serotype 3 receptor targeted oncolytic adenovirus

Gene Therapy volume 14, pages 1380–1388 (2007)Cite this article

Abstract

Arming oncolytic adenoviruses with therapeutic transgenes and enhancing transduction of tumor cells are useful strategies for eradication of advanced tumor masses. Herpes simplex virus thymidine kinase (TK) together with ganciclovir (GCV) has been promising when coupled with viruses featuring low oncolytic potential, but their utility is unknown in the context of highly effective infectivity-enhanced viruses. We constructed Ad5/3-Δ24-TK-GFP, a serotype 3 receptor-targeted, Rb/p16 pathway-selective oncolytic adenovirus, where a fusion gene encoding TK and green fluorescent protein (GFP) was inserted into 6.7K/gp19K-deleted E3 region. Ad5/3-Δ24-TK-GFP killed ovarian cancer cells effectively, which correlated with GFP expression. Delivery of GCV immediately after infection abrogated viral replication, which might have utility as a safety switch. Due to the bystander effect, killing of some cell lines in vitro was enhanced by GCV regardless of timing. In murine models of metastatic ovarian cancer, Ad5/3-Δ24-TK-GFP improved antitumor efficacy over the respective replication-deficient virus with GCV. However, GCV did not further enhance efficacy of Ad5/3-Δ24-TK-GFP in vivo. Simultaneous detection of tumor load and virus replication with bioluminescence and fluorescence imaging provided insight into the in vivo kinetics of oncolysis. In summary, TK/GCV may not add antitumor activity in the context of highly potent oncolysis.

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Acknowledgements

We thank Dr Sari Pesonen for statistical advice. This work was supported by Helsinki Biomedical Graduate School, University of Helsinki, EU FP6 THERADPOX and APOTHERAPY, HUCH Research Funds (EVO), Sigrid Juselius Foundation, Academy of Finland, Emil Aaltonen Foundation, Finnish Cancer Society, Biomedicum Helsinki Foundation, Research Foundation for Virus Diseases and Schering Research Foundation/Finnish Oncology Association (unrestricted).

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Authors and Affiliations

  1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Haartman Institute, University of Helsinki, Helsinki, Finland

    M Raki, T Hakkarainen, G J Bauerschmitz, M Särkioja, A Kanerva & A Hemminki

  2. Department of Oncology and HUSLAB Laboratory of Transplantation Pathology, Helsinki University Central Hospital, Helsinki, Finland

    M Raki, T Hakkarainen, G J Bauerschmitz, M Särkioja, A Kanerva & A Hemminki

  3. Department of Obstetrics and Gynecology, Duesseldorf University Medical Center, Heinrich-Heine University, Germany

    G J Bauerschmitz

  4. Biostatistics and Bioinformatics Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    R A Desmond

  5. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

    A Kanerva

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  1. M Raki
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Correspondence to A Hemminki.

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Supplementary information accompanies the paper on Gene Therapy web site (http://www.nature.com/gt)

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Raki, M., Hakkarainen, T., Bauerschmitz, G. et al. Utility of TK/GCV in the context of highly effective oncolysis mediated by a serotype 3 receptor targeted oncolytic adenovirus. Gene Ther 14, 1380–1388 (2007). https://doi.org/10.1038/sj.gt.3302992

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