Centre for Personalised Cancer Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
Oncol Rep. 2013 Jul;30(1):471-7. doi: 10.3892/or.2013.2454. Epub 2013 May 13.
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.
本研究评估了 drozitumab 的疗效，drozitumab 是一种针对死亡受体 5 (DR5) 的人源单克隆激动性抗体，是一种针对骨和软组织肉瘤的靶向治疗的新方法。在体外的一组肉瘤细胞系和人类肉瘤患者样本中，评估了 drozitumab 作为单一疗法或与 Nutlin-3a 联合治疗的抗肿瘤活性。通过敲低实验研究了 p53 作为 drozitumab 细胞毒性调节剂的核心作用。Nutlin-3a 预先激活 p53 通路可上调 DR5，随后使肉瘤细胞系和人类肉瘤标本对 drozitumab 的促凋亡作用敏感。沉默 p53 可显著降低 DR5 mRNA 表达，从而阻断 drozitumab 诱导的细胞凋亡。我们的研究首次对使用 p53 激活剂与 drozitumab 联合治疗进行了临床前评估，以进一步提高肉瘤对 DR5 抗体治疗的细胞毒性作用的敏感性。
