TERT promoter-driven adenovirus vector for cancer gene therapy via systemic injection.
Adenovirus vectors (Adv) are used widely in cancer gene therapy research. However, the clinical application of Adv currently is limited to local, intratumoral administration; systemic administration leads to redundant transgene expression in the liver and subsequent hepatotoxicity. Here we replaced the conventional cytomegalovirus (CMV) promoter of Adv with a tumor-specific telomere reverse transcriptase (TERT) promoter, to restrict expression of the Adv-transduced transgene to tumor tissue alone. We evaluated the therapeutic and side effects after systemic administration of Adv expressing herpes simplex virus thymidine kinase (Ad-HSVtk) in mice bearing Meth-A tumors. Although systemically injected CMV promoter-driven Ad-HSVtk lacked therapeutic effect, mice injected with 2x10(11) viral particles containing TERT promoter-driven Ad-HSVtk showed inhibited tumor growth and prolonged survival with minimal side effects. Our results suggest that Adv in which transgene expression is driven by the TERT promoter are a promising prototype of tumor-targeting vectors for effective and safe cancer gene therapy.
Yao
Xinglei
X
Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan.
Yoshioka
Yasuo
Y
Eto
Yusuke
Y
Morishige
Tomohiro
T
Okada
Yuka
Y
Mizuguchi
Hiroyuki
H
Mukai
Yohei
Y
Okada
Naoki
N
Nakagawa
Shinsaku
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001835:Body Weight; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007267:Injections; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
C509186:TERT protein, human; D019098:Telomerase