title: Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma.
abstract: Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumor hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumors. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS.
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, South Australia, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, South Australia, Australia.
authors.forename: Agatha
authors.initials: A
authors.lastname: Labrinidis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, South Australia, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Zinonos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, South Australia, Australia.
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, South Australia, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Panagopoulos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, South Australia, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: DeNichilo
authors.affiliation: Discipline of Surgery, Haematology - Oncology, Breast Biology Cancer Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ingman
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.affiliation: School of Medical Sciences, Myeloma Research Laboratory Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Faculty of Health Science, University of Adelaide, Australia.
authors.forename: Andrew C W
authors.initials: ACW
authors.lastname: Zannettino
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, South Australia, Australia. Electronic address: andreas.evdokiou@adelaide.edu.au.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010752:Phosphoramide Mustards / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302
keywords: Chemotherapy; Hypoxia; Metastasis; Osteosarcoma; TH-302