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Novel chimeric gene promoters responsive to hypoxia and ionizing radiation

Greco, Olga, Marples, Brian, Dachs, G.U., Williams, Kaye J., Patterson, Adam V., Scott, Simon D. (2002) Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. Gene Therapy, 9 (20). pp. 1403-1411. ISSN 0969-7128. E-ISSN 1476-5462. (doi:10.1038/ (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:80)

Language: English

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Despite being an adverse prognostic factor in radiotherapy, hypoxia represents a physiological difference that can be exploited for selective cancer gene therapy. In this study gene therapy vectors responsive to both hypoxia and ionizing radiation (IR) were developed. Gene expression was regulated by novel, synthetic promoters containing hypoxia responsive elements (HREs) from the erythropoietin (Epo), the phosphoglycerate kinase 1 (PGK1) and the vascular endothelial growth factor (VEGF) genes, and IR-responsive CArG elements from the early growth response (Egr) 1 gene. All chimeric promoters could be activated by hypoxia and/or IR-treatment, and selectively control marker gene expression in human T24 bladder carcinoma and MCF-7 mammary carcinoma cells. Importantly, enhancers containing combinations of HREs and CArG elements were able to respond to both triggering treatments, with the Epo HRE/CArG combination proving to be the most responsive and robust. The Epo HRE/CArG enhancer could effectively control a suicide gene therapy strategy by selectively sensitizing hypoxic and/or irradiated cells expressing the enzyme horseradish peroxidase (HRP) to the prodrug indole-3-acetic acid (IAA). These data indicate that the use of such chimeric promoters may effectively regulate therapeutic gene expression within the tumor microenvironment in gene therapy strategies aimed at addressing the problem of hypoxia in radiotherapy.

Item Type: Article
DOI/Identification number: 10.1038/
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Susan Davies
Date Deposited: 19 Dec 2007 17:55 UTC
Last Modified: 16 Nov 2021 09:39 UTC
Resource URI: (The current URI for this page, for reference purposes)

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