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Adenoviral targeting of gene expression to tumors

Cancer Gene Therapy volumeĀ 17,Ā pages 375ā€“386 (2010)Cite this article

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Abstract

Using biochemical, imaging and histological methods, we employed transcriptional targeting to increase the specificity of tumor gene expression in vivo for intravenously administered recombinant adenovirus vectors. Surprisingly, the relative specificity of tumor expression in comparison with other tissues was increased for a constitutively expressing recombinant adenovirus, AdCMVLuc, by simply reducing the viral dose. Even at lower doses, however, the high frequency of viral infection and transgene expression in the liver using constitutive promoters still represents a substantial problem. To further augment tumor specificity, we constructed a series of adenoviruses expressing luciferase from several other promoters and tested their ability to selectively transcribe genes in tumor cells, both in vitro and in vivo. Constitutively active viral promoters (RSV, SRĪ±) varied widely in their tumor selectivity, but hypoxia-responsive promoters (carbonic anhydrase 9, PAI-1, SOD2 and several chimeric constructs) showed the most tumor-selective expression. Our results show that tumor targeting to HT1080 fibrosarcomas was readily achieved using transcriptional targeting mechanisms. We attribute the relatively high level of gene transfer and expression in HT1080 tumors in vivo to increased viral access to the tumor, presumably due to discontinuities in tumor vasculature and augmented expression from stress-responsive promoters in the hypoxic and inflammatory tumor microenvironment.

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Acknowledgements

We wish to thank Caroline Humphries, Julie Poirot and Fred Kruse for technical help with recombinant virus construction and preparation, Paul Card for preparation of the manuscript and Phil Thorpe for critically reading it. Julia Kozlitina and Alex Pertsemlidis provided statistical advice and performed the Jonckheereā€“Terpstra analysis. Optical imaging was facilitated by the UTSouthwestern Small Animal Imaging Research Program funded by NCI U24 CA126608. This work was supported by a Texas Higher Education Coordinating Board Advanced Technology Program grant and by NIH R01 CA115935 to RDG.

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  1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    R T Hogg,Ā J A GarciaĀ &Ā R D Gerard

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  1. R T Hogg
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Correspondence to R D Gerard.

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Hogg, R., Garcia, J. & Gerard, R. Adenoviral targeting of gene expression to tumors. Cancer Gene Ther 17, 375ā€“386 (2010). https://doi.org/10.1038/cgt.2010.1

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