Spatial and temporal control of gene therapy using ionizing radiation.
Activation of transcription of the Egr-1 gene by X-rays is regulated by the promoter region of this gene. We linked the radiation-inducible promoter region of the Egr-1 gene to the gene encoding the radiosensitizing and tumoricidal cytokine, tumour necrosis factor-alpha (TNF-alpha) and used a replication-deficient adenovirus to deliver the Egr-TNF construct to human tumours growing in nude mice. Combined treatment with Ad5.Egr-TNF and 5,000 cGy (rad) resulted in increased intratumoral TNF-alpha production and increased tumour control compared with treatment with Ad5.Egr-TNF alone or with radiation alone. The increase in tumour control was achieved without an increase in normal tissue damage when compared to tissue injury from radiation alone. Control of gene transcription by ionizing radiation in vivo represents a novel method of spatial and temporal regulation of gene-based medical treatments.
Hallahan
D E
DE
Department of Radiation and Cellular Oncology, University of Chicago, Illinois, USA.
Mauceri
H J
HJ
Seung
L P
LP
Dunphy
E J
EJ
Wayne
J D
JD
Hanna
N N
NN
Toledano
A
A
Hellman
S
S
Kufe
D W
DW
Weichselbaum
R R
RR
D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000528:radiation effects*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D017874:Immediate-Early Proteins; D007150:Immunohistochemistry; D007822:Laryngeal Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D017921:Mastadenovirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009368:Neoplasm Transplantation; D011839:Radiation, Ionizing; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha