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The combination of i-leader truncation and gemcitabine improves oncolytic adenovirus efficacy in an immunocompetent model

Cancer Gene Therapy volume 21, pages 68–73 (2014)Cite this article

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Abstract

Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.

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Acknowledgements

We thank Dr Miriam Bazan Peregrino for extensive revision of the manuscript. CPS was supported by a master fellowship from ‘La Caixa’ and a predoctoral fellowship (PFIS) granted by the ‘Instituto de Salud Carlos III’ FI08/00163. This work was supported by a BIO2011-30299-C02-01 grant from the ‘Ministerio de Educación y Ciencia’ of the Government of Spain (RA) and a 2009SGR283 research grant from the ‘Generalitat de Catalunya’ (RA).

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Authors and Affiliations

  1. Translational Research Laboratory, Institut d’Investigació Biomèdica de Bellvitge-Institut Català d’Oncologia (IDIBELL-ICO), Barcelona, Spain

    C Puig-Saus, E Laborda, A Rodríguez-García, M Cascalló, R Moreno & R Alemany

  2. Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain

    E Laborda

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  1. C Puig-Saus
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Correspondence to R Alemany.

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Puig-Saus, C., Laborda, E., Rodríguez-García, A. et al. The combination of i-leader truncation and gemcitabine improves oncolytic adenovirus efficacy in an immunocompetent model. Cancer Gene Ther 21, 68–73 (2014). https://doi.org/10.1038/cgt.2013.85

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