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Telomerase-Specific Replication-Selective Virotherapy for Human Cancer
Abstract
Purpose: 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. Experimental Design: 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.
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“We developed a novel telomerase-dependent replicative adenovirus type 5 vector (Telomelysin, OBP-301) in which E1A and E1B genes, required for adenoviral replication, were transcribed under the hTERT promoter.(106)”
From Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [106]
In the citing paper
“Indeed, Telomelysin could efficiently kill head and neck, lung, esophageal, pancreatic, hepatic, prostate, and cervical cancers, as well as melanoma, sarcoma, and mesothelioma cells.(106,110)”
From Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [106]
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Self-citation
Metadata
- Authors
- Kawashima, T., Kagawa, S., Kobayashi, N., Shirakiya, Y., Umeoka, T., Teraishi, F., Taki, M., Kyo, S., Tanaka, N., & Fujiwara, T.
- Affiliations
- Okayama University (JP)
- Kanazawa University (JP)
- Venue
- Clinical Cancer Research
- Published
- 2004-01-01
- Volume
- 10
- Issue
- 1
- Pages
- 285-292
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2128023051
- Cited by
- 262
- References
- 30
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 10 · 2023: 19 · 2022: 9 · 2021: 16 · 2020: 15 · 2019: 3 · 2018: 10 · 2017: 7 · 2016: 13 · 2015: 7 · 2014: 5 · 2013: 12 · 2012: 15
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Keywords
- telomerase, human telomerase reverse transcriptase, replication-competent adenovirus, virotherapy, hTERT promoter, internal ribosome entry site, anticancer activity, intratumoral injection, tumor growth inhibition
- MeSH terms
- Adenoviridae, Adenoviridae Infections, Animals, Carcinoma, Non-Small-Cell Lung, Colonic Neoplasms, Cytopathogenic Effect, Viral, Female, Fibroblasts, Genetic Vectors, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Promoter Regions, Genetic, Virus Replication, Gene Expression Regulation, Viral, Gene Expression Regulation, Neoplastic, Apoptosis, Adenovirus E1 Proteins, Telomerase, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, In Vitro Techniques
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