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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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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DOI: https://doi.org/10.1038/sj.gt.3302604
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