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Type: Journal article
Title: Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma
Author: Liapis, V.
Labrinidis, A.
Zinonos, I.
Hay, S.
Ponomarev, V.
Panagopoulos, V.
DeNichilo, M.
Ingman, W.
Atkins, G.
Findlay, D.
Zannettino, A.
Evdokiou, A.
Citation: Cancer Letters, 2015; 357(1):160-169
Publisher: Elsevier Ireland
Issue Date: 2015
ISSN: 0304-3835
Statement of
Vasilios Liapis, Agatha Labrinidis, Irene Zinonos, Shelley Hay, Vladimir Ponomarev, Vasilios Panagopoulos, Mark DeNichilo, Wendy Ingman, Gerald J. Atkins, David M. Findlay, Andrew C.W. Zannettino, Andreas Evdokiou
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: Hypoxia; TH-302; Osteosarcoma; Metastasis; Chemotherapy
Rights: Crown Copyright © 2014 Published by Elsevier Ireland Ltd. All rights reserved
RMID: 0030016418
DOI: 10.1016/j.canlet.2014.11.020
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Appears in Collections:Surgery publications

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