Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer

Dong Liu, Toru Kojima, Masaaki Ouchi, Shinji Kuroda, Yuichi Watanabe, Yuuri Hashimoto, Hideki Onimatsu, Yasuo Urata, Toshiyoshi Fujiwara

Research output: Contribution to journalArticle

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Abstract

A phase I dose-escalation study of telomerase-specific oncolytic adenovirus, OBP-301 (Telomelysin), is now under way in the United States to assess feasibility and to characterize its pharmacokinetics in patients with advanced solid tumors. The present preclinical study investigates whether OBP-301 and a chemotherapeutic agent that is commonly used for lung cancer treatment, gemcitabine, are able to enhance antitumor effects in vitro and in vivo. The antitumor effects of OBP-301 infection and gemcitabine were evaluated by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt assay. In vivo antitumor effects of intratumoral injection of OBP-301 in combination with systemic administration of gemcitabine were assessed on nu/nu mice s.c. xenografted with human lung tumors. OBP-301 infection combined with gemcitabine resulted in very potent synergistic cytotoxicity in human lung cancer cells. The three human lung cancer cell lines treated with OBP-301 for 24 hours tended to accumulate in S phase compared with controls. The proportion of cells in S phase increased from 43.85% to 56.41% in H460 cells, from 46.72% to 67.09% in H322 cells, and from 38.22% to 57.67% in H358 cells. Intratumoral injection of OBP-301 combined with systemic administration of gemcitabine showed therapeutic synergism in human lung tumor xenografts. Our data suggest that the combination of OBP-301 and gemcitabine enhances the antitumor effects against human lung cancer. We also found that the synergistic mechanism may be due to OBP-301-mediated cell cycle accumulation in S phase. These results have important implications for the treatment of human lung cancer.

Original languageEnglish
Pages (from-to)980-987
Number of pages8
JournalMolecular Cancer Therapeutics
Volume8
Issue number4
DOIs
Publication statusPublished - Apr 1 2009

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gemcitabine
Oncolytic Virotherapy
Telomerase
Lung Neoplasms
S Phase
Neoplasms
Lung
Injections
Infection
Heterografts
Adenoviridae
Cell Cycle
Therapeutics
Pharmacokinetics
Salts
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer. / Liu, Dong; Kojima, Toru; Ouchi, Masaaki; Kuroda, Shinji; Watanabe, Yuichi; Hashimoto, Yuuri; Onimatsu, Hideki; Urata, Yasuo; Fujiwara, Toshiyoshi.

In: Molecular Cancer Therapeutics, Vol. 8, No. 4, 01.04.2009, p. 980-987.

Research output: Contribution to journalArticle

Liu, Dong ; Kojima, Toru ; Ouchi, Masaaki ; Kuroda, Shinji ; Watanabe, Yuichi ; Hashimoto, Yuuri ; Onimatsu, Hideki ; Urata, Yasuo ; Fujiwara, Toshiyoshi. / Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer. In: Molecular Cancer Therapeutics. 2009 ; Vol. 8, No. 4. pp. 980-987.
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