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Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity.

Authors
  • Stine, Kimo C1
  • Wahl, Elizabeth C2
  • Liu, Lichu2
  • Skinner, Robert A3
  • VanderSchilden, Jaclyn3
  • Bunn, Robert C1
  • Montgomery, Corey O3
  • Aronson, James1, 2, 3
  • Becton, David L1
  • Nicholas, Richard W3
  • Swearingen, Christopher J1, 4
  • Suva, Larry J3
  • Lumpkin, Charles K5, 6
  • 1 Departments of Pediatrics, University of Arkansas for Medical Sciences, Arkansas.
  • 2 Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Arkansas.
  • 3 Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
  • 4 Pediatric Biostatistics, Arkansas Children's Hospital Research Institute, Arkansas.
  • 5 Departments of Pediatrics, University of Arkansas for Medical Sciences, Arkansas. [email protected]
  • 6 Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Arkansas. [email protected]
Type
Published Article
Journal
Journal of Orthopaedic Research®
Publisher
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2016
Volume
34
Issue
10
Pages
1716–1724
Identifiers
DOI: 10.1002/jor.23192
PMID: 26867804
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The majority of Osteosarcoma (OS) patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. These protocols include distraction osteogenesis (DO), which is characterized by direct new bone formation. Cisplatin (CDP) is extensively used for OS chemotherapy and recent studies, using a mouse DO model, have demonstrated that CDP has profound negative effects on bone repair. Recent oncological therapeutic strategies are based on the use of standard cytotoxic drugs plus an assortment of biologic agents. Here we demonstrate that the previously reported CDP-associated inhibition of bone repair can be modulated by the administration of a small molecule p53 inducer (nutlin-3). The effects of nutlin-3 on CDP osteotoxicity were studied using both pre- and post-operative treatment models. In both cases the addition of nutlin-3, bracketing CDP exposure, demonstrated robust and significant bone sparing activity (p < 0.01-0.001). In addition the combination of nutlin-3 and CDP induced equivalent OS tumor killing in a xenograft model. Collectively, these results demonstrate that the induction of p53 peri-operatively protects bone healing from the toxic effects of CDP, while maintaining OS toxicity. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1716-1724, 2016. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

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