Radiation to control transgene expression in tumors.
Significant evidence has accumulated indicating that certain genes are induced by ionising radiation. An implication of this observation is that their promoter regions include radiation-responsive sequences. These sequences have been isolated in the promoter of several genes including Erg-1, p21/WAF-1, GADD45alpha and t-PA. The mechanism by which radiation induces gene expression remains unclear but involves putative binding sites for selected transcription factors and/or p53. Consensus CC(A/T)6GG sequences have been localized in the Erg-1 promoter and are referred to as serum response elements or CArG elements. The tandem combination of CArG elements has been shown to improve gene expression levels, with a 9-copy motif conferring maximum inducibility. The response of these genes to ionising radiation appears to follow a sigmoid relationship with time and dose. Therapeutic induction of suicide genes and significant cytotoxicity can be achieved at clinically relevant x-rays doses both in vitro and in vivo but was found to be cell-type dependent. Radiation-inducible gene therapy can be potentially enhanced by exploiting hypoxia through the inclusion of hypoxia-response element motifs in the expression cassette, the use of the anaerobic bacteria or the use of neutron irradiation. These results are encouraging and provide significant evidence that gene therapy targeted to the radiation field is a reasonably attractive therapeutic option and could help overcome hypoxic radioresistant tumors.
Marignol
Laure
L
Deportment of Haematology and Academic Unit of Clinical and Molecular Oncology, Institute of Molecular Medicine, St James's Hospital and Trinity College, Dublin, Ireland. marignol@tcd.ie
Coffey
M
M
Hollywood
D
D
Lawler
M
M
D018797:Cell Cycle Proteins / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000528:radiation effects*; D010959:Tissue Plasminogen Activator / Q000235:genetics; D019076:Transgenes; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051766:Early Growth Response Protein 1; D009687:Nuclear Proteins; D010959:Tissue Plasminogen Activator; C493956:CDKN1A protein, human; C497325:EGR1 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins