Anticancer efficacy of the hypoxia-activated prodrug evofosfamide is enhanced in combination with proapoptotic receptor agonists against osteosarcoma.

Abstract

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia also leads to treatment opportunities as demonstrated by the development of compounds that target regions of hypoxia within tumors. Evofosfamide is a hypoxia-activated prodrug that is created by linking the hypoxia-seeking 2-nitroimidazole moiety to the cytotoxic bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions of tumors, the DNA cross-linking toxin, Br-IPM, is released leading to cell death. This study assessed the anticancer efficacy of evofosfamide in combination with the Proapoptotic Receptor Agonists (PARAs) dulanermin and drozitumab against human osteosarcoma in vitro and in an intratibial murine model of osteosarcoma. Under hypoxic conditions in vitro, evofosfamide cooperated with dulanermin and drozitumab, resulting in the potentiation of cytotoxicity to osteosarcoma cells. In contrast, under the same conditions, primary human osteoblasts were resistant to treatment. Animals transplanted with osteosarcoma cells directly into their tibiae developed mixed osteosclerotic/osteolytic bone lesions and consequently developed lung metastases 3 weeks post cancer cell transplantation. Tumor burden in the bone was reduced by evofosfamide treatment alone and in combination with drozitumab and prevented osteosarcoma-induced bone destruction while also reducing the growth of pulmonary metastases. These results suggest that evofosfamide may be an attractive therapeutic agent, with strong anticancer activity alone or in combination with either drozitumab or dulanermin against osteosarcoma.

• Authors: Vasilios Liapis, Aneta Zysk, Mark DeNichilo, Irene Zinonos, Shelley Hay, Vasilios Panagopoulos, Alexandra Shoubridge, Christopher Difelice, Vladimir Ponomarev, Wendy Ingman, Gerald J Atkins, David M Findlay, Andrew C W Zannettino, Andreas Evdokiou
• Journal: Cancer medicine (Cancer Med) Vol. 6 Issue 9 Pg. 2164-2176 (Sep 2017) ISSN: 2045-7634 [Electronic] United States
• PMID: 28799237 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Nitroimidazoles
• Phosphoramide Mustards
• Prodrugs
• TH 302
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• drozitumab

Topics

• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Bone Neoplasms (drug therapy)
• Cell Hypoxia
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Humans
• Nitroimidazoles (administration & dosage, pharmacology)
• Osteosarcoma (drug therapy)
• Phosphoramide Mustards (administration & dosage, pharmacology)
• Prodrugs (administration & dosage, pharmacology)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays