Telomerase-Specific Replication-Selective Virotherapy for Human Cancer

Takeshi Kawashima, Shunsuke Kagawa, Naoya Kobayashi, Yoshiko Shirakiya, Tatsuo Umeoka, Fuminori Teranishi, Masaki Taki, Satoru Kyo, Noriaki Tanaka, Toshiyoshi Fujiwara

Research output: Contribution to journalArticle

152 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)285-292
Number of pages8
JournalClinical Cancer Research
Volume10
Issue number1 I
DOIs
Publication statusPublished - Jan 1 2004

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Telomerase
Adenoviridae
Neoplasms
Human Adenoviruses
Fibroblasts
Oncogenic Viruses
Heterografts
Mental Competency
Carcinogenesis
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Telomerase-Specific Replication-Selective Virotherapy for Human Cancer. / Kawashima, Takeshi; Kagawa, Shunsuke; Kobayashi, Naoya; Shirakiya, Yoshiko; Umeoka, Tatsuo; Teranishi, Fuminori; Taki, Masaki; Kyo, Satoru; Tanaka, Noriaki; Fujiwara, Toshiyoshi.

In: Clinical Cancer Research, Vol. 10, No. 1 I, 01.01.2004, p. 285-292.

Research output: Contribution to journalArticle

Kawashima, T, Kagawa, S, Kobayashi, N, Shirakiya, Y, Umeoka, T, Teranishi, F, Taki, M, Kyo, S, Tanaka, N & Fujiwara, T 2004, 'Telomerase-Specific Replication-Selective Virotherapy for Human Cancer', Clinical Cancer Research, vol. 10, no. 1 I, pp. 285-292. https://doi.org/10.1158/1078-0432.CCR-1075-3
Kawashima, Takeshi ; Kagawa, Shunsuke ; Kobayashi, Naoya ; Shirakiya, Yoshiko ; Umeoka, Tatsuo ; Teranishi, Fuminori ; Taki, Masaki ; Kyo, Satoru ; Tanaka, Noriaki ; Fujiwara, Toshiyoshi. / Telomerase-Specific Replication-Selective Virotherapy for Human Cancer. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 1 I. pp. 285-292.
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AU - Umeoka, Tatsuo

AU - Teranishi, Fuminori

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N2 - 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.

AB - 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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