Abstract
Ionising radiation induces the expression of a number of radiation-responsive genes and there is current interest in exploiting this to regulate the expression of exogenous therapeutic genes in gene therapy strategies for cancer. However, the radiation-responsive promoters used in these approaches are often associated with low and transient levels of therapeutic gene expression. We describe here a novel radiation-triggered molecular switching device based on promoter elements from the radiation-responsive Egr-1 gene and the cre-LoxP site-specific recombination system of the P1 bacteriophage. Using this system, a single, minimally toxic dose of radiation induced cre-mediated excision of a lox-P flanked stop cassette in a silenced expression vector and this resulted in amplified levels of CMV-promoter-driven expression of the exogenous tumour-sensitising gene, HSV-tk. This strategy could be used in combination with targeted delivery and tumour-specific promoters to elicit the tumour-targeted and prolonged expression of a variety of tumour-sensitising genes and provide an unprecedented level of control and tumour selectivity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1121-1125 |
| Number of pages | 5 |
| Journal | Gene Therapy |
| Volume | 7 |
| Issue number | 13 |
| DOIs | |
| State | Published - Jan 1 2000 |
| Externally published | Yes |
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Keywords
- CRE recombinase
- Ganciclovir
- HSVtk
- Molecular switch
- Radiation-responsive elements
- Radiotherapy
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
Cite this
A radiation-controlled molecular switch for use in gene therapy of cancer. / Scott, S. D.; Marples, Brian; Hendry, J. H.; Lashford, L. S.; Embleton, M. J.; Hunter, R. D.; Howell, A.; Margison, G. P.
In: Gene Therapy, Vol. 7, No. 13, 01.01.2000, p. 1121-1125.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A radiation-controlled molecular switch for use in gene therapy of cancer
AU - Scott, S. D.
AU - Marples, Brian
AU - Hendry, J. H.
AU - Lashford, L. S.
AU - Embleton, M. J.
AU - Hunter, R. D.
AU - Howell, A.
AU - Margison, G. P.
PY - 2000/1/1
Y1 - 2000/1/1
N2 - Ionising radiation induces the expression of a number of radiation-responsive genes and there is current interest in exploiting this to regulate the expression of exogenous therapeutic genes in gene therapy strategies for cancer. However, the radiation-responsive promoters used in these approaches are often associated with low and transient levels of therapeutic gene expression. We describe here a novel radiation-triggered molecular switching device based on promoter elements from the radiation-responsive Egr-1 gene and the cre-LoxP site-specific recombination system of the P1 bacteriophage. Using this system, a single, minimally toxic dose of radiation induced cre-mediated excision of a lox-P flanked stop cassette in a silenced expression vector and this resulted in amplified levels of CMV-promoter-driven expression of the exogenous tumour-sensitising gene, HSV-tk. This strategy could be used in combination with targeted delivery and tumour-specific promoters to elicit the tumour-targeted and prolonged expression of a variety of tumour-sensitising genes and provide an unprecedented level of control and tumour selectivity.
AB - Ionising radiation induces the expression of a number of radiation-responsive genes and there is current interest in exploiting this to regulate the expression of exogenous therapeutic genes in gene therapy strategies for cancer. However, the radiation-responsive promoters used in these approaches are often associated with low and transient levels of therapeutic gene expression. We describe here a novel radiation-triggered molecular switching device based on promoter elements from the radiation-responsive Egr-1 gene and the cre-LoxP site-specific recombination system of the P1 bacteriophage. Using this system, a single, minimally toxic dose of radiation induced cre-mediated excision of a lox-P flanked stop cassette in a silenced expression vector and this resulted in amplified levels of CMV-promoter-driven expression of the exogenous tumour-sensitising gene, HSV-tk. This strategy could be used in combination with targeted delivery and tumour-specific promoters to elicit the tumour-targeted and prolonged expression of a variety of tumour-sensitising genes and provide an unprecedented level of control and tumour selectivity.
KW - CRE recombinase
KW - Ganciclovir
KW - HSVtk
KW - Molecular switch
KW - Radiation-responsive elements
KW - Radiotherapy
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U2 - 10.1038/sj.gt.3301223
DO - 10.1038/sj.gt.3301223
M3 - Article
VL - 7
SP - 1121
EP - 1125
JO - Gene Therapy
JF - Gene Therapy
SN - 0969-7128
IS - 13
ER -