Novel chimeric gene promoters responsive to hypoxia and ionizing radiation
Greco, O., Marples, B., Dachs, G.U., Williams, K.J., 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 0969-7128 (print), 1476-5462 (electronic) (doi:10.1038/sj.gt.3301823)Full text not available from this repository.
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.
|Additional Information:|| Access to this article is free|
|Uncontrolled Keywords:||radiotherapy, HRE, CArG element, GDEPT, HRP/IAA|
|Subjects:||R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)|
T Technology > TP Chemical technology
|School / Department / Research Groups:||Medway School of Pharmacy|
|Last Modified:||29 Jun 2012 16:08|
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