Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin.
Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin.
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人类激动的跟踪受体抗体mapatumumab和lexatumumab诱导恶性间皮瘤中凋亡，并与顺铂协同作用。
DOI：
10.1186/1476-4598-6-66
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发表时间：
2007-10-22
期刊：
影响因子：
37.3
通讯作者：
Stahel, Rolf A.
中科院分区：
文献类型：
--
作者：
Belyanskaya, Larisa L.;Marti, Thomas M.;Hopkins-Donaldson, Sally;Kurtz, Stefanie;Felley-Bosco, Emanuela;Stahel, Rolf A.
恶性胸膜间皮瘤 (MPM) 的发病率与接触石棉有关，预测表明，到 2020 年，西欧每年因 MPM 死亡的人数将会增加。尽管化疗和多模式治疗取得了进展，但 MPM 仍然是一种预后不良的疾病。通过肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 或靶向 TRAIL 受体 1 (TRAIL-R1) 或 TRAIL-R2 的激动性单克隆抗体诱导细胞凋亡被认为是一种有前途的癌症治疗方法。我们比较了 13 个 MPM 细胞系或原代培养物对 TRAIL 以及针对 TRAIL-R1 (Mapatumumab) 和 TRAIL-R2 (Lexatumumab) 的两种全人激动性单克隆抗体的敏感性，并检查了 TRAIL 受体抗体诱导的 MPM 细胞系对顺铂的敏感性。我们发现 MPM 细胞对 TRAIL、Mapatumumab 和 Lexatumumab 的敏感性差异很大，并且与 TRAIL 受体表达无关。在表达两种受体的 MPM 细胞中，TRAIL-R2 对死亡受体介导的细胞凋亡的贡献大于 TRAIL-R1。顺铂与 Mapatumumab 或 Lexatumumab 的组合可协同抑制细胞生长并增强细胞凋亡。此外，与相反顺序相比，用顺铂预处理然后用 Mapatumumab 或 Lexatumumab 导致显着更高的细胞毒性作用。用抗氧化剂 N-乙酰半胱氨酸预处理细胞可显着消除组合诱导的细胞生长抑制。我们的结果表明，顺铂继之以 Mapatumumab 或 Lexatumumab 的序贯给药在 MPM 患者的治疗中值得研究。
The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy. We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine. Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.
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