Cited by 263Virus-based gene therapy researchTelomeres, Telomerase, and SenescenceBacterial Cancer Therapy

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Telomerase-Specific Replication-Selective Virotherapy for Human Cancer

Kawashima, Takeshi, Kagawa, Shunsuke, Kobayashi, Naoya, Shirakiya, Yoshiko, Umeoka, Tatsuo, Teraishi, Fuminori, Taki, Masaki, Kyo, Satoru, Tanaka, Noriaki, Fujiwara, Toshiyoshi·2004·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-1075-3

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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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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)
ORCID: Kagawa, Shunsuke
Kobayashi, Naoya
Teraishi, Fuminori
Kyo, Satoru
Fujiwara, Toshiyoshi
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2004-01-01
Volume: 10
Issue: 1
Pages: 285-292
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-1075-3
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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Telomerase-Specific Replication-Selective Virotherapy for Human Cancer

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