Diagnostic and therapeutic application of telomerase-specific oncolytic adenoviral agents.
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. 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. We further modified the E3 region of OBP-301 to contain green fluorescent protein (GFP) gene for monitoring viral replication (TelomeScan, OBP-401). When TelomeScan was intratumorally injected into human tumors orthotopically implanted into the rectum in mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that TelomeScan causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This article reviews recent highlights in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the telomerase-specific oncolytic adenoviruses.
Fujiwara
Toshiyoshi
T
Center for Gene and Cell Therapy, Okayama University Hospital, Okayama 700-8558, Japan. toshi_f@md.okayamau.ac.jp
Urata
Yasuo
Y
Tanaka
Noriaki
N
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D005822:Genetic Vectors; D023281:Genomics / Q000379:methods; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy*; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
D049452:Green Fluorescent Proteins; C509186:TERT protein, human; D019098:Telomerase