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A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

Abstract

The E2F-1 promoter has been used to confer tumor-selective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F–pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-Δ24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The Δ24 deletion avoids a loop of E2F-mediated self-activation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.

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Acknowledgements

We thank Blanca Luena and Eduard Serra for their technical assistance. We also thank pathologist Teresa Serrano from the Department of Pathology of the Hospital Universitari de Bellvitge, Spain, for procurement of human liver biopsies. JJ Rojas was supported by a predoctoral fellowship (FI) granted by the Generalitat de Catalunya. This work was supported by BIO2008-04692-C03-01 from the Ministerio de Ciencia y Tecnología of the Government of Spain (RA), EU 6th FP research contract 18700 (Theradpox, RA), 2005 SGR 00727 from the Departament d’Universitats, Recerca i Societat de la Informació of the Generalitat de Catalunya and by Mutua Madrileña Medical Research Foundation. R. Alemany is a member of the Network of Cooperative Research on Cancer (C03-10), Instituto de Salud Carlos III of the Ministerio de Sanidad y Consumo, Government of Spain. A Hemminki is K. Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute and supported by the European Research Council, HUCH Research Funds (EVO), Sigrid Juselius Foundation, Academy of Finland, Biocentrum Helsinki and Finnish Cancer Society.

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Correspondence to R Alemany.

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Rojas, J., Cascallo, M., Guedan, S. et al. A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses. Gene Ther 16, 1441–1451 (2009). https://doi.org/10.1038/gt.2009.103

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