[Oncostatin M gene therapy in mice bearing lung adenocarcinoma xenograft using a hypoxia/radiation dual-sensitive promoter].
OBJECTIVE
To improve the efficacy of radiogenetic therapy for lung cancer, a hypoxia/radiation dual-sensitive promoter was constructed to enhance the expression of oncostatin M (OSM) in transfected cells exposed to radiation under hypoxia.


METHODS
The chimeric promoter HRE-Egr was generated by insertion of hypoxia response elements (HREs) upstream of the Early growth response gene-1 (Egr-1) promoter. OSM expression vector was constructed by cloning HRE-Egr promoter upstream of OSM gene, which was transfected into A549 cells. The expression of OSM in transfected cells exposed to irradiation and(or) hypoxia was analyzed, and the relative survival rate of transfected cells exposed to the above conditions was tested. To examine the efficacy of this HRE-Egr-OSM gene therapy in vivo, the tumor suppression effects were investigated in 40 nude mice bearing lung adenocarcinoma xenograft.


RESULTS
Expression of OSM gene in transfected cells exposed 6 Gy irradiation was markedly increased under hypoxia. A gene therapy experiment in vitro showed that the survival rate of transfected cells exposed to radiation under hypoxia was obviously decreased with comparison of cells under normoxia. HRE-Egr promoter transfected tumors regressed significantly after a combination therapy of irradiation and HRE-Egr transfection in all mice (n = 10), and six tumors disappeared in 3 weeks without any side effects.


CONCLUSIONS
The data indicate that tumor targeted expression of OSM gene under the control of a hypoxia/radiation dual-sensitive promoter represents a novel strategy for safe and effective gene therapy of lung carcinoma and might have clinical application in the future.
Wang
Wei-dong
WD
Cancer Center of People's Liberation Army, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Chen
Zheng-tang
ZT
Li
De-zhi
DZ
Duan
Yu-zhong
YZ
Wang
Zhi-xin
ZX
Cao
Zheng-huai
ZH
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003037:Cobalt Radioisotopes; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D053683:Oncostatin M; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection
D003037:Cobalt Radioisotopes; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D014157:Transcription Factors; D053683:Oncostatin M