Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma Journal Article


Authors: Liapis, V.; Labrinidis, A.; Zinonos, I.; Hay, S.; Ponomarev, V.; Panagopoulos, V.; Denichilo, M.; Ingman, W.; Atkins, G. J.; Findlay, D. M.; Zannettino, A. C. W.; Evdokiou, A.
Article 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.
Keywords: osteosarcoma; controlled study; human cell; doxorubicin; drug efficacy; drug potentiation; nonhuman; chemotherapy; mouse; metastasis; apoptosis; tumor volume; animal experiment; animal model; in vivo study; drug potency; in vitro study; drug selectivity; animalia; hypoxia; cancer inhibition; lung metastasis; cell hypoxia; drug cytotoxicity; ex vivo study; bone destruction; osteoblast; tibia; bone atrophy; osteosclerosis; human; female; article; ic50; th-302; evofosfamide; osteosarcoma cell line
Journal Title: Cancer Letters
Volume: 357
Issue: 1
ISSN: 0304-3835
Publisher: Elsevier Ireland Ltd.  
Date Published: 2015-01-01
Start Page: 160
End Page: 169
Language: English
DOI: 10.1016/j.canlet.2014.11.020
PROVIDER: scopus
PUBMED: 25444931
PMCID: PMC4574867
DOI/URL:
Notes: Export Date: 2 February 2015 -- Source: Scopus
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  1. Vladimir Ponomarev
    124 Ponomarev