Inhibition of Repair of Radiation-Induced DNA Damage Enhances Gene Expression from Replication-Defective Adenoviral Vectors

Hingorani, Mohan and White, Christine L. and Merron, Andrew and Peerlinck, Inge and Gore, Martin E. and Slade, Andrew and Scott, Simon and Nutting, Christopher M. and Pandha, Hardev S. and Melcher, Alan A. and Vile, Richard G. and Vassaux, Georges and Harrington, Kevin J. (2008) Inhibition of Repair of Radiation-Induced DNA Damage Enhances Gene Expression from Replication-Defective Adenoviral Vectors. Cancer Research, 68 (23). pp. 9771-9778. ISSN 0008-5472. (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Radiation has been shown to up-regulate gene expression from adenoviral vectors in previous studies. In the current study, we show that radiation-induced dsDNA breaks and subsequent signaling through the mitogen-activated protein kinase (MAPK) pathway are responsible, at least in part, for this enhancement of transgene expression both in vitro and in vivo. Inhibitors of ataxia-telangiectasia-mutated, poly(ADPribose) polymerise-mutated, and DNA-dependent protein kinase (DNA-M)-mediated DNA repair were shown to maintain dsDNA breaks (gamma H2AX foci) by fluorescence-activated cell sorting and microscopy. Inhibition of DNA repair was associated with increased green fluorescent protein (GFP) expression from a replication-defective adenoviral vector (Ad-CMV-GFP). Radiation-induced up-regulation of gene expression was abrogated by inhibitors of MAPK (PD980059 and U0126) and phosphatidylinositol 3-kinase (LY294002) but not by p38 MAPK inhibition. A reporter plasmid assay in which GFP was under the transcriptional control of artificial Egr-1 or cytomegalovirus promoters showed that the DNA repair inhibitors increased GFP expression only in the context of the Egr-1 promoter. In vivo administration of a water-soluble DNA-PK inhibitor (KU0060648) was shown to maintain luciferase expression in HCT116 xenografts after intratumoral delivery of Ad-RSV-Luc. These data have important implications for therapeutic strategies involving multimodality use of radiation, targeted drugs, and adenoviral gene delivery and provide a framework for evaluating potential advantageous combinatorial effects. [Cancer Res 2008;68(23):9771-8]

Item Type: Article
Subjects: R Medicine
Divisions: Faculties > Science Technology and Medical Studies > Medway School of Pharmacy
Depositing User: Jane Griffiths
Date Deposited: 20 Apr 2009 12:49
Last Modified: 24 Jun 2014 15:39
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