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

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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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  2. X Wang
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  3. A Hurtado Picó
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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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