Telomerase-specific replication-selective virotherapy for human cancer.
OBJECTIVE
Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells.


METHODS
We constructed an adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (TRAD)], in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human cancer cells in vitro and in vivo.


RESULTS
TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying s.c. human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors, despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, noninjected tumors was demonstrated.


CONCLUSIONS
Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.
Kawashima
Takeshi
T
Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Kagawa
Shunsuke
S
Kobayashi
Naoya
N
Shirakiya
Yoshiko
Y
Umeoka
Tatsuo
T
Teraishi
Fuminori
F
Taki
Masaki
M
Kyo
Satoru
S
Tanaka
Noriaki
N
Fujiwara
Toshiyoshi
T
D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000473:pathology / Q000628:therapy / Q000821:virology; D017498:Adenovirus E1 Proteins / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D003588:Cytopathogenic Effect, Viral; D005260:Female; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D017498:Adenovirus E1 Proteins; D019098:Telomerase