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Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

Cancer Gene Therapy volume 10, pages 791–802 (2003)Cite this article

Abstract

Replication-competent adenoviral vectors hold the promise to be more efficient gene delivery vehicles than their replication-deficient counterparts, but they are also associated with a higher risk for adverse effects, especially in light of the fact that there is no established effective therapy for serious, disseminated adenovirus infection. To assess whether the therapeutic options to inhibit adenoviral replication can be enhanced by expressing a suicide gene, we examined the antiadenoviral effects of 15 drugs against wild-type adenovirus type 5 (Ad5) and an Ad5-based replication-competent vector expressing herpes simplex virus-1 thymidine kinase (HSV-tk) (Ad.OW34) using a real-time polymerase chain reaction -based assay and flow cytometry. Ad5 and Ad.OW34 were highly susceptible to the fluorinated pyrimidine analogs 5-fluoro-2′-deoxyuridine (FUdR), 5-fluorouridine (FUR), and trifluorothymidine (TFT), with a mean 50% inhibitory concentration (IC50) ranging from 0.12 to 0.32 μM. The mean IC50 of ribavirin and cidofovir (CDV) for Ad5, the most frequently used drugs to treat adenovirus disease, was 6.87 and 3.19 μM, respectively. In contrast to Ad5, the Ad.OW34 vector was susceptible to (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdU, IC50 0.09 μM), ganciclovir (GCV, IC50 0.19 μM), and acyclovir (ACV, IC50 32.04 μM). Additionally, we demonstrated in an animal model that Ad.OW34 vector replication can be inhibited significantly by GCV, CDV, and TFT by 35.2, 7.7, and 3.7-fold, respectively, compared to untreated animals. The observed antiadenoviral effects were primarily not through cell killing, since the in vitro 50% cytotoxic concentrations (CC50) were more than 1000 times higher than the antiadenoviral IC50 of the drugs examined, even in cells stably expressing HSV-tk. Since for HSV-tk-dependent inhibition of adenoviral vectors, stability of HSV-tk expression is crucial, we examined Ad.OW34 vector stability, by passaging the vector 10 times serially in the presence of 10 μM GCV. The HSV-tk/GCV system neither changed the susceptibility of Ad.OW34 to GCV significantly nor detectable vector rearrangements occurred, suggesting that the system might be suitable as a fail-safe mechanism to stop adenoviral vector replication.

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Abbreviations

E1, E3, Adenovirus early region 1 and 3:

Respectively

CMV-IE:

Cytomegalovirus immediate-early

HSV-tk:

Herpes simplex virus-1 thymidine kinase

GFP:

Green fluorescent protein

Ad5:

Wild-type human adenovirus serotype 5

MOI:

multiplicity of infection

PFU:

plaque forming unit

qPCR:

quantitative polymerase chain reaction

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Acknowledgements

We are grateful to Norbert W Bischofberger, Gilead Sciences (Foster City, CA) for providing cidofovir. We thank Vera Siegmund for cloning and sequence analysis of the HSV-tk gene and her critical review of the manuscript. Furthermore, we are thankful to Klaus Sure for his support to establish the qPCR and Cathrin S Walter for her critical review of this manuscript and stimulating discussions. This work was supported by grants from Deutsche Forschungsgemeinschaft, Dr. Mildred Scheel Stiftung für Krebsforschung, and Forschungsförderung Ruhr-Universität Bochum Nedizinischen Fakultät (FoRUM) to OW. DH was supported by Sophia & Fritz Heinemann Stiftung and CJ by Konrad-Adenauer-Stiftung.

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  1. Abteilung für Molekulare und Medizinische Virologie, Ruhr-Universität Bochum, Bldg. MA, Rm. 6/40, Bochum, D-44801, Germany

    Oliver Wildner, Dennis Hoffmann, Christian Jogler & Klaus Überla

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  1. Oliver Wildner
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  2. Dennis Hoffmann
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  3. Christian Jogler
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  4. Klaus Überla
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Correspondence to Oliver Wildner.

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Wildner, O., Hoffmann, D., Jogler, C. et al. Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs. Cancer Gene Ther 10, 791–802 (2003). https://doi.org/10.1038/sj.cgt.7700638

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  • DOI: https://doi.org/10.1038/sj.cgt.7700638

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