Novel chimeric gene promoters responsive to hypoxia and ionizing radiation.

Greco, O. and Marples, B. and Dachs, G.U. and Williams, K.J. and Patterson, A.V. and Scott, S.D. (2002) Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. Gene Therapy, 9 (20). pp. 1403-1411. ISSN 0167-2738. (Access to this publication is restricted)

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Abstract

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
Subjects: Q Science
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences > Biomedical Research Group
Depositing User: Sue Davies
Date Deposited: 19 Dec 2007 17:55
Last Modified: 05 Sep 2011 23:19
Resource URI: http://kar.kent.ac.uk/id/eprint/80 (The current URI for this page, for reference purposes)
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