Novel chimeric gene promoters responsive to hypoxia and ionizing radiation

O. Greco, Brian Marples, G. U. Dachs, K. J. Williams, A. V. Patterson, S. D. Scott

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1403-1411
Number of pages9
JournalGene Therapy
Volume9
Issue number20
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

Fingerprint

Ionizing Radiation
Genetic Therapy
Genes
Erythropoietin
Gene Expression
Radiotherapy
Phosphoglycerate Kinase
Tumor Microenvironment
Hypoxia
Neoplasm Genes
Prodrugs
Horseradish Peroxidase
Suicide
Vascular Endothelial Growth Factor A
Urinary Bladder
Therapeutics
Breast Neoplasms
Carcinoma
Enzymes
Growth

Keywords

  • CArG element
  • GDEPT
  • HRE
  • HRP/IAA
  • Radiotherapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Greco, O., Marples, B., Dachs, G. U., Williams, K. J., Patterson, A. V., & Scott, S. D. (2002). Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. Gene Therapy, 9(20), 1403-1411. https://doi.org/10.1038/sj.gt.3301823

Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. / Greco, O.; Marples, Brian; Dachs, G. U.; Williams, K. J.; Patterson, A. V.; Scott, S. D.

In: Gene Therapy, Vol. 9, No. 20, 01.01.2002, p. 1403-1411.

Research output: Contribution to journalArticle

Greco, O, Marples, B, Dachs, GU, Williams, KJ, Patterson, AV & Scott, SD 2002, 'Novel chimeric gene promoters responsive to hypoxia and ionizing radiation', Gene Therapy, vol. 9, no. 20, pp. 1403-1411. https://doi.org/10.1038/sj.gt.3301823
Greco, O. ; Marples, Brian ; Dachs, G. U. ; Williams, K. J. ; Patterson, A. V. ; Scott, S. D. / Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. In: Gene Therapy. 2002 ; Vol. 9, No. 20. pp. 1403-1411.
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