title: Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.forename: Jo
authors.initials: J
authors.lastname: Hasei
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kunisada
authors.forename: Aki
authors.initials: A
authors.lastname: Yoshida
authors.forename: Yuuri
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yoshida
authors.forename: Futoshi
authors.initials: F
authors.lastname: Uno
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morimoto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ozaki
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003588:Cytopathogenic Effect, Viral; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D011991:Receptors, Virus / Q000378:metabolism; D012509:Sarcoma / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D019098:Telomerase