[Experimental study on lung carcinoma-targeted suicide gene therapy induced by irradiation].
OBJECTIVE
To improve the efficacy and selectivity of gene therapy for lung carcinoma, a strategy was designed for suicide gene therapy in conjunction with irradiation therapy, by constructing a plasmid tgEgr-HyTK in which HSV-TK gene was driven by the early growth responsive gene-1 (Egr-1) promoter.


METHODS
The radio-inducible suicide gene was constructed by insertion of Egr-1 promoter upstream of the HSV-TK gene. The expressions of HSV-TK in lung carcinoma cell lines A549 which were infected with tgEgr-HyTK and exposed to different doses of gamma-ray irradiation were analyzed, and the relative survival rates of cells in presence of prodrug ganciclovir (GCV) were tested. The tumor suppression effects were investigated in 40 nude mice bearing lung tumors to examine the efficacy of this Egr-TK gene therapy in vivo.


RESULTS
Expression of HSV-TK gene in lung carcinoma cells infected with tgEgr-HyTK plasmids was markedly increased in a radiation dose-dependent manner. A gene therapy experiment in vitro showed that tgEgr-HyTK transduced lung carcinoma cells became highly sensitive to GCV after irradiation, but not without irradiation. tgEgr-HyTK transfected tumors regressed significantly after a combination therapy of irradiation and GCV in all mice (n = 10), and five tumors disappeared in 3 weeks without any side effect.


CONCLUSIONS
The data indicate that tumor targeted expression of HSV-TK gene under the control of a radio-inducible promoter represents a novel strategy for safe and effective gene therapy of lung carcinoma, which may have clinical application in the future.
Wang
Wei-dong
WD
Cancer Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Chen
Zheng-tang
ZT
Li
De-zhi
DZ
Duan
Yu-zhong
YZ
Cao
Zheng-huai
ZH
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000818:Animals; D045744:Cell Line, Tumor; D003037:Cobalt Radioisotopes / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000528:radiation effects; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; 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; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / 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; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D013937:Thymidine Kinase; D015774:Ganciclovir