Transcriptional control of viral gene therapy by cisplatin.
Ionizing radiation (IR) and radical oxygen intermediates (ROIs) activate the early growth response-1 (Egr1) promoter through specific cis-acting sequences termed CArG elements. Ad.Egr.TNF.11D, a replication-deficient adenoviral vector containing CArG elements cloned upstream of the cDNA for human recombinant TNF-alpha was used to treat human esophageal adenocarcinoma and rat colon adenocarcinoma cells in culture and as xenografts in athymic nude mice. Cisplatin, a commonly used chemotherapeutic agent, causes tumor cell death by producing DNA damage and generating ROIs. The present studies demonstrate induction of TNF-alpha production in tumor cells and xenografts treated with the combination of Ad.Egr.TNF.11D and cisplatin. The results show that the Egr1 promoter is induced by cisplatin and that this induction is mediated in part through the CArG elements. These studies also demonstrate an enhanced antitumor response without an increase in toxicity following treatment with Ad.Egr.TNF.11D and cisplatin, compared with either agent alone. Chemo-inducible cancer gene therapy thus provides a means to control transgene expression while enhancing the effectiveness of commonly used chemotherapeutic agents.
Park
James O
JO
Department of Surgery, University of Chicago, Chicago, Illinois, USA.
Lopez
Carlos A
CA
Gupta
Vinay K
VK
Brown
Charles K
CK
Mauceri
Helena J
HJ
Darga
Thomas E
TE
Manan
Abdullah
A
Hellman
Samuel
S
Posner
Mitchell C
MC
Kufe
Donald W
DW
Weichselbaum
Ralph R
RR
D000230:Adenocarcinoma / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1; D004938:Esophageal Neoplasms / Q000628:therapy; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D051381:Rats; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; 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; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin