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Type: Journal article
Title: Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy
Author: Pishas, K.
Neuhaus, S.
Clayer, M.
Adwal, A.
Brown, M.
Evdokiou, A.
Callen, D.
Neilsen, P.
Citation: Oncology Reports: an international journal devoted to fundamental and applied research in oncology, 2013; 30(1):471-477
Publisher: Spandidos Publications
Issue Date: 2013
ISSN: 1021-335X
Statement of
Pishas, K.I., Neuhaus, S.J., Clayer, M.T., Adwal, A., Brown, M.P., Evdokiou, A., Callen, D.F., Neilsen, P.M.
Abstract: The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin-3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre-clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy.
Keywords: Drozitumab
Rights: Copyright status unknown
DOI: 10.3892/or.2013.2454
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