Potent anti-tumor activity of telomerase-dependent and HSV-TK armed oncolytic adenovirus for non-small cell lung cancer in vitro and in vivo.
BACKGROUND
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related mortality, any improvements in therapeutic strategies are urgently required. In this study we generated a novel 'suicide gene' armed oncolytic adenoviral vector and investigated its antitumor effect both in vitro and in vivo.


METHODS
Since the up-regulated expression of human telomerase reverse transcriptase (hTERT) is a hallmark of alltypes of NSCLC, we chose hTERT promoter to transcriptionally control E1A gene expression to obtain adenoviral replication in NSCLC. In order to further enhance anti-tumor effect of this oncolytic adenoviral vector, we inserted a 'suicide gene' i.e. Herpes Simplex Virus Thymidine Kinase (HSV-TK) into oncolytic adenoviral vector to engineer a novel armed oncolytic adenoviral vector 'Ad.hTERT-E1A-TK'.


RESULTS
Ad.hTERT-E1A-TK efficiently killed different types of tumor cells including two types of NSCLC cells in vitro, causing no damage to normal primary fibroblasts. Furthermore, Ad.hTERT-E1A-TK infection combined with administration of prodrug gancyclovir (GCV) resulted in more potent cytotoxicity on NSCLC cells, and synergistically suppressed human NSCLC tumor growth in nude mice.


CONCLUSIONS
The results from this study showed that Ad.hTERT-E1A-TK/GCV could be a potent but safe anti-tumor strategy for NSCLC biotherapy.
Zhang
Ju-Feng
JF
Central Experimental Laboratory, First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, PR China.
Wei
Fang
F
Wang
Hui-Ping
HP
Li
Hui-Ming
HM
Qiu
Wei
W
Ren
Peng-Kang
PK
Chen
Xia-Fang
XF
Huang
Qian
Q
D000256:Adenoviridae / Q000235:genetics*; D000257:Adenoviridae Infections / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000008:administration & dosage; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D018139:Simplexvirus / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*
D013937:Thymidine Kinase; C509186:TERT protein, human; D019098:Telomerase; D015774:Ganciclovir