Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter.
Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. For targeting cancer cells, there is a need for tissue- or cell-specific promoters that can express in diverse tumor types and are silent in normal cells. Recent advances in molecular biology have fostered remarkable insights into the molecular basis of neoplasm. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site (IRES). Telomelysin 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 cells lacking telomerase activity. Thus, the hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. This article reviews recent findings in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the hTERT promoter.
Fujiwara
Toshiyoshi
T
Center for Gene and Cell Therapy, Okayama University Hospital, Okayama 700-8558, Japan. toshi_f@md.okayama-u.ac.jp
Urata
Yasuo
Y
Tanaka
Noriaki
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003131:Combined Modality Therapy; D003952:Diagnostic Imaging / Q000379:methods; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*; D014158:Transcription, Genetic; D016896:Treatment Outcome; D014779:Virus Replication
D009363:Neoplasm Proteins; C509186:TERT protein, human; D019098:Telomerase