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(E)-5-(2-Bromovinyl)-2′-deoxyuridine potentiates ganciclovir-mediated cytotoxicity on herpes simplex virus-thymidine kinase–expressing cells

Cancer Gene Therapy volume 8, pages 388–396 (2001)Cite this article

Abstract

Tumor cells expressing the thymidine kinase gene of the herpes simplex virus (HSV-tk) are rendered highly susceptible to the cytotoxic effects of different antiherpes drugs. In an attempt to enhance cytotoxicity of this therapeutic approach in glioma and other tumor cell lines transduced with the HSV-tk gene, we evaluated tumor cell killing following co-administration of two different prodrugs metabolized by HSV-tk, (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU), and ganciclovir (GCV). In 8 of 12 cell lines investigated, addition of BVDU in concentrations showing no cytotoxic effect or only limited cytotoxicity could enhance GCV-mediated cell killing by as much as one order of magnitude. In co-cultures consisting of HSV-tk+ (9L STK) and HSV-tk− (9L wild-type) cells, we also observed potentiation of GCV-mediated cytotoxicity in the presence of BVDU, suggesting strongly enhanced bystander cell killing. BVDU is thought to exert its cytotoxic effect through inhibition of thymidylate synthase activity or by incorporation into replicating DNA. Both effects could be observed in all HSV-tk–expressing cells investigated, including cell lines which did not exhibit cytotoxicity after incubation with BVDU. These findings argue against current concepts of BVDU-mediated cytotoxicity in HSV-tk–expressing cells. Taken together, our data suggest that gene therapy utilizing prodrug activating enzymes may be rendered more effective by simultaneous treatment with two different prodrugs metabolized by the same enzyme. Cancer Gene Therapy (2001) 8, 388–396

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Acknowledgements

This work was supported by grants from the Preuss Foundation, Anne and Jason Farber Foundation, and Betz Foundation and from the National Institute of Health Grant no. 5 P01 CA13525. W. H. was supported by a fellowship from the Deutsche Forschungsgemeinschaft. We thank H. Meissner and S. Zapf for help with tissue culture.

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Authors and Affiliations

  1. Preuss Laboratory for Molecular Neuro-Oncology, Brain Tumor Research Center, HSE-722, University of California, San Francisco, 94143-0520, California

    Wolfgang Hamel & Mark A Israel

  2. Klinik für Neurochirurgie, Christian Albrechts Universität zu Kiel, Kiel, 24106, Germany

    Wolfgang Hamel & H. Maximilian Mehdorn

  3. Neurochirurgische Klinik, Universitäts-Krankenhaus Eppendorf, Hamburg, 20246, Germany

    Dorothea Zirkel & Manfred Westphal

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  1. Wolfgang Hamel
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Correspondence to Wolfgang Hamel.

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Hamel, W., Zirkel, D., Mehdorn, H. et al. (E)-5-(2-Bromovinyl)-2′-deoxyuridine potentiates ganciclovir-mediated cytotoxicity on herpes simplex virus-thymidine kinase–expressing cells. Cancer Gene Ther 8, 388–396 (2001). https://doi.org/10.1038/sj.cgt.7700322

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