TY - JOUR
T1 - Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity
AU - Stine, Kimo C.
AU - Wahl, Elizabeth C.
AU - Liu, Lichu
AU - Skinner, Robert A.
AU - VanderSchilden, Jaclyn
AU - Bunn, Robert C.
AU - Montgomery, Corey O.
AU - Aronson, James
AU - Becton, David L.
AU - Nicholas, Richard W.
AU - Swearingen, Christopher J.
AU - Suva, Larry J.
AU - Lumpkin, Charles K.
N1 - Publisher Copyright:
© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
KW - chemotherapy
KW - cisplatin
KW - distraction osteogenesis
KW - limb salvage
KW - nutlin-3
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U2 - 10.1002/jor.23192
DO - 10.1002/jor.23192
M3 - Article
C2 - 26867804
AN - SCOPUS:84991109502
SN - 0736-0266
VL - 34
SP - 1716
EP - 1724
JO - Journal of Orthopaedic Research
JF - Journal of Orthopaedic Research
IS - 10
ER -