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: 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
• Journal: Cancer letters (Cancer Lett) Vol. 357 Issue 1 Pg. 160-169 (Feb 01 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25444931 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Nitroimidazoles
• Phosphoramide Mustards
• Prodrugs
• TH 302

Topics

• Animals
• Apoptosis (drug effects)
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Cell Hypoxia (physiology)
• Female
• Humans
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Nitroimidazoles (pharmacokinetics, pharmacology)
• Osteosarcoma (drug therapy, metabolism, pathology)
• Phosphoramide Mustards (pharmacokinetics, pharmacology)
• Prodrugs (pharmacokinetics, pharmacology)