Biteau, K., Guiho, R., Chatelais, M. et al. (5 more authors) (2016) L-MTP-PE and zoledronic acid combination in osteosarcoma: pre-clinical evidence of positive therapeutic combination for clinical transfer. American Journal of Cancer Research, 6 (3). 0025208. pp. 677-689. ISSN 2156-6976
Abstract
Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneicial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic beneit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 µg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the irst time a signiicant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a irst proof-of-principle for clinical application in osteosarcoma patients.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | AJCR Copyright © 2010-present, All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711, USA |
Keywords: | Osteosarcoma; liposomal mifamurtide; zoledronic acid; inhibition of lung metastases development; bone protection |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 03 May 2016 14:41 |
Last Modified: | 03 May 2016 14:41 |
Published Version: | http://www.ajcr.us/files/ajcr0025208.pdf |
Status: | Published |
Publisher: | e-Century Publishing |
Refereed: | Yes |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:99174 |