Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas

Tsuyoshi Sasaki, Hiroshi Tazawa, Jo Hasei, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Shunsuke Kagawa, Yuki Morimoto, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Purpose: Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells. Experimental Design: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas. Results: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells. Conclusions: A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas.

Original languageEnglish
Pages (from-to)1828-1838
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number7
DOIs
Publication statusPublished - Apr 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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