Second Medical Oncology Unit, Istituto Oncologico Veneto, Padua, Italy.
Second Medical Oncology Unit, Istituto Oncologico Veneto, Padua, Italy.
J Thorac Oncol. 2014 Jul;9(7):1008-1017. doi: 10.1097/JTO.0000000000000198.
Malignant pleural mesothelioma (MPM) is an aggressive, currently incurable tumor with increasing incidence in industrialized countries. Tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which induces cancer cell death through extrinsic apoptotic pathway, while sparing normal cells. The aim of this study was to investigate the antitumor activity of recombinant human Apo2L/TRAIL (dulanermin) in combination with chemotherapy in MPM in vitro and in vivo.
In the present studies, we employed a panel of MPM cell lines to test the antitumor activity of recombinant human Apo2L/TRAIL (T) in combination with carboplatin and pemetrexed (CP) in vitro and SCID mice.
Results demonstrated a significant increase of apoptosis in cell lines treated with CPT compared with those receiving CP or T as single agents. This synergistic effect was dependent on the ability of CP to increase the expression of the TRAIL receptors DR4 and DR5 in a p53 manner. The CPT combination was also effective in blocking the growth of MPM cell lines in a SCID mice preclinical model.
CPT increases MPM cell death in vitro and in vivo compared with CP. In vitro results suggest that chemotherapy sensitizes MPM to TRAIL-dependent apoptosis through p53 activation and subsequent upregulation of DRs.
恶性胸膜间皮瘤（MPM）是一种侵袭性的、目前无法治愈的肿瘤，在工业化国家的发病率正在上升。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是 TNF 家族的一员，它通过外在凋亡途径诱导癌细胞死亡，而不损伤正常细胞。本研究旨在探讨重组人 Apo2L/TRAIL（dulanermin）与化疗联合治疗 MPM 的体内外抗肿瘤活性。
在本研究中，我们采用一组 MPM 细胞系来测试重组人 Apo2L/TRAIL（T）与卡铂和培美曲塞（CP）联合治疗体外和 SCID 小鼠的抗肿瘤活性。
结果表明，与单独接受 CP 或 T 治疗的细胞系相比，CPT 处理的细胞系中凋亡明显增加。这种协同作用依赖于 CP 以 p53 方式增加 TRAIL 受体 DR4 和 DR5 的表达的能力。CPT 联合治疗在 SCID 小鼠临床前模型中也能有效抑制 MPM 细胞系的生长。
CPT 与 CP 相比，能增加 MPM 细胞的体外和体内死亡。体外结果表明，化疗通过 p53 激活和随后上调 DRs 使 MPM 对 TRAIL 依赖性凋亡敏感。
