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The radiation-inducible pE9 promoter driving inducible nitric oxide synthase radiosensitizes hypoxic tumour cells to radiation

Coulter, J.A., McCarthy, H.O., Worthington, J., Robson, T., Scott, Simon D., Hirst, D.G. (2008) The radiation-inducible pE9 promoter driving inducible nitric oxide synthase radiosensitizes hypoxic tumour cells to radiation. Gene Therapy, 15 (7). pp. 495-503. ISSN 0969-7128. (doi:10.1038/gt.2008.7) (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)

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. (Contact us about this Publication)
Official URL
https://doi.org/10.1038/gt.2008.7

Abstract

Driving high-level transgene expression in a tumour-specific manner remains a key requirement in the development of cancer gene therapy. We have previously demonstrated the strong anticancer effects of generating abnormally high levels of intracellular NOâ?¢ following the overexpression of the inducible nitric oxide synthase (iNOS) gene. Much of this work has focused on utilizing exogenously activated promoters, which have been primarily induced using X-ray radiation. Here we further examine the potential of the pE9 promoter, comprising a combination of nine CArG radio-responsive elements, to drive the iNOS transgene. Effects of X-ray irradiation on promoter activity were compared in vitro under normoxic conditions and various degrees of hypoxia. The pE9 promoter generated high-level transgene expression, comparable with that achieved using the constitutively driven cytomegalovirus promoter. Furthermore, the radio-resistance of radiation-induced fibrosarcoma-1 (RIF-1) mouse sarcoma cells exposed to 0.1 and 0.01% O2 was effectively eliminated following transfection with the pE9/iNOS construct. Significant inhibition of tumour growth was also observed in vivo following direct intratumoural injection of the pE9/iNOS construct compared to empty vector alone (P<0.001) or to a single radiation dose of 10Gy (P<0.01). The combination of both therapies resulted in a significant 4.25 day growth delay compared to the gene therapy treatment alone (P<0.001). In summary, we have demonstrated the potential of the pE9/iNOS construct for reducing radio-resistance conferred by tumour cell hypoxia in vitro and in vivo, with greater tumour growth delay observed following the treatment with the gene therapy construct as compared with radiotherapy alone.

Item Type: Article
DOI/Identification number: 10.1038/gt.2008.7
Additional information: Unmapped bibliographic data: PY - 2008/// [EPrints field already has value set] AD - School of Pharmacy, McClay Research Centre, Queen's University, Belfast, Northern Ireland, United Kingdom [Field not mapped to EPrints] AD - Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom [Field not mapped to EPrints] AD - Medway School of Pharmacy, University of Kent, Kent, United Kingdom [Field not mapped to EPrints] JA - Gene Ther. [Field not mapped to EPrints]
Uncontrolled keywords: inducible nitric oxide synthase, nitric oxide, oxygen, animal experiment, animal model, antineoplastic activity, article, cancer gene therapy, cancer inhibition, cell hypoxia, controlled study, Cytomegalovirus, expression vector, female, fibrosarcoma, gene activity, gene construct, gene expression, gene overexpression, genetic transfection, in vitro study, in vivo study, mouse, nonhuman, priority journal, promoter region, radiation dose, radiosensitization, sarcoma cell, transgene, tumor cell, X ray, Animals, Cell Hypoxia, Cell Line, Tumor, Combined Modality Therapy, Cytomegalovirus, Female, Fibrosarcoma, Gene Therapy, Mice, Mice, Inbred C3H, Neoplasms, Nitric Oxide Synthase Type II, Nitrites, Promoter Regions (Genetics), Radiation-Sensitizing Agents, Transfection, Xenograft Model Antitumor Assays, Cytomegalovirus
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Simon Scott
Date Deposited: 01 Dec 2017 14:32 UTC
Last Modified: 01 Jul 2019 13:36 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/29432 (The current URI for this page, for reference purposes)
Scott, Simon D.: https://orcid.org/0000-0002-8290-0461
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