A radiation-controlled molecular switch for use in gene therapy of cancer.
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.
Scott
S D
SD
Cancer Research Campaign Section of Genome Damage and Repair, Paterson Institute for Cancer Research, Christie Hospital (NHS) Trust, Manchester, UK.
Marples
B
B
Hendry
J H
JH
Lashford
L S
LS
Embleton
M J
MJ
Hunter
R D
RD
Howell
A
A
Margison
G P
GP
D000998:Antiviral Agents / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D003587:Cytomegalovirus / Q000235:genetics; D005434:Flow Cytometry; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins; D006801:Humans; D019426:Integrases / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D009369:Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014764:Viral Proteins
D000998:Antiviral Agents; D008164:Luminescent Proteins; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase; C045073:Cre recombinase; D019426:Integrases; D015774:Ganciclovir