title: Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models.
abstract: Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. Evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross-linking effector, Br-IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer-induced bone destruction was measured using micro-CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth. Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. Evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone.
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, 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, 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, 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, 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, New York.
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, 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, Woodville, South Australia, Australia.
authors.forename: Aneta
authors.initials: A
authors.lastname: Zysk
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide Woodville, Woodville, South Australia, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: DeNichilo
authors.affiliation: Discipline of Surgery, School of Medicine at The Queen Elizabeth Hospital, University of Adelaide, Woodville, South Australia, Australia.|Robinson Research 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, Adelaide, South Australia, Australia.
authors.forename: Andrew C W
authors.initials: AC
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, Woodville, South Australia, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D010752:Phosphoramide Mustards / Q000008:administration & dosage* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; C552526:TH 302; D017239:Paclitaxel
keywords: Breast cancer; TH-302; chemotherapy; evofosfamide; hypoxia; tumor growth