Dual responsive promoters to target therapeutic gene expression to radiation-resistant hypoxic tumor cells.
Int J Radiat Oncol Biol Phys
; 62(1): 213-22, 2005 May 01.
Article
em En
| MEDLINE
| ID: mdl-15850924
ABSTRACT
PURPOSE:
Tumor hypoxia is unequivocally linked to poor radiotherapy outcome. This study aimed to identify enhancer sequences that respond maximally to a combination of radiation and hypoxia for use in genetic radiotherapy approaches. METHODS AND MATERIALS The influence of radiation (5 Gy) and hypoxia (1% O2) on reporter-gene expression driven by hypoxia (HRE) and radiation (Egr-1) responsive elements was evaluated in tumor cells grown as monolayers or multicellular spheroids. Hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha protein expression was monitored in parallel.RESULTS:
Of the sequences tested, an HRE from the phosphoglycerate kinase-1 gene (PGK-18[5+]) was maximally induced in response to hypoxia plus radiation in all 5 cell lines tested. The additional radiation treatment afforded a significant increase in the induction of PGK-18[5+] compared with hypoxia alone in 3 cell lines. HIF-1alpha/2alpha were induced by radiation but combined hypoxia/radiation treatment did not yield a further increase. The dual responsive nature of HREs was maintained when spheroids were irradiated after delivery of HRE constructs in a replication-deficient adenovirus.CONCLUSIONS:
Hypoxia-responsive enhancer element sequences are dually responsive to combined radiation and hypoxic treatment. Their use in genetic radiotherapy in vivo could maximize expression in the most radio-resistant population at the time of radiation and also exploit microenvironmental changes after radiotherapy to yield additional switch-on.
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Base de dados:
MEDLINE
Assunto principal:
Fosfoglicerato Quinase
/
Tolerância a Radiação
/
Hipóxia Celular
/
Regulação da Expressão Gênica
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article