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Tamoxifen-regulated adenoviral E1A chimeras for the control of tumor selective oncolytic adenovirus replication in vitro and in vivo

Gene Therapy volume 13, pages 173–186 (2006)Cite this article

Abstract

Pharmacological control is a desirable safety feature of oncolytic adenoviruses (oAdV). It has recently been shown that oAdV replication may be controlled by drug-dependent transcriptional regulation of E1A expression. Here, we present a novel concept that relies on tamoxifen-dependent regulation of E1A activity through functional linkage to the mutated hormone-binding domain of the murine estrogen receptor (Mer). Four different E1A-Mer chimeras (ME, EM, EΔNLSM, MEM) were constructed and inserted into the adenoviral genome under control of a lung-specific surfactant protein B promoter. The highest degree of regulation in vitro was seen for the corresponding oAdVs Ad.EΔNLSM and Ad.MEM, which exhibited an up to 100-fold higher oAdV replication in the presence as compared with the absence of 4-OH-tamoxifen. Moreover, destruction of nontarget cells was six- and 13-fold reduced for Ad.EΔNLSM and Ad.MEM, respectively, as compared with Ad.E. Further investigations supported tamoxifen-dependent regulation of Ad.EΔNLSM and Ad.MEM in vivo. Induction of Ad.EΔNLSM inhibited growth of H441 lung tumors as efficient as a control oAdV expressing E1A. EΔNLSM and the MEM chimeras can be easily inserted into a single vector genome, which extends their application to existing oAdVs and strongly facilitates in vivo application.

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Abbreviations

4-OH-Tam:

4-OH-tamoxifen

Mer:

mutated hormone-binding domain of murine estrogen receptor

oAdV:

oncolytic adenovirus

HBD:

hormone-binding domain

MOI:

multiplicity of infection

PFU:

plaque-forming units

Dox:

doxycycline

TRE:

tetracycline response element.

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Acknowledgements

This work was supported by a grant from the Wilhelm Sander-Stiftung to HF (2002.007.1) and by the Cardiovascular Research Center and the Research Committee of Charité – Universitätsmedizin Berlin.

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  1. W Poller and H Fechner: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Cardiology and Pneumology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    I Sipo, X Wang, A Hurtado Picó, L Suckau, W Poller & H Fechner

  2. Department of Virology, Institute of Infectious Diseases, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    S Weger

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  1. I Sipo
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Correspondence to H Fechner.

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Sipo, I., Wang, X., Hurtado Picó, A. et al. Tamoxifen-regulated adenoviral E1A chimeras for the control of tumor selective oncolytic adenovirus replication in vitro and in vivo. Gene Ther 13, 173–186 (2006). https://doi.org/10.1038/sj.gt.3302604

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