Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice.
Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice.
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DOI：
10.1158/1078-0432.ccr-14-3195
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发表时间：
2015-10-15
期刊：
影响因子：
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通讯作者：
Fidler IJ
中科院分区：
文献类型：
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作者：
Kim SJ;Lee HJ;Kim MS;Choi HJ;He J;Wu Q;Aldape K;Weinberg JS;Yung WK;Conrad CA;Langley RR;Lehembre F;Regenass U;Fidler IJ
本研究的目的是确定星形胶质细胞和脑内皮细胞是否通过内皮素依赖的信号机制保护胶质瘤细胞免受替莫唑胺(TMZ)的影响，并观察双重内皮素受体拮抗剂Macitentan在人脑胶质母细胞瘤原位模型中的治疗效果。在化学保护试验中，我们评估了几种内皮素受体拮抗剂抑制星形胶质细胞和脑内皮细胞对TMZ诱导的胶质瘤细胞保护的能力。我们比较了裸鼠原位移植LN-229胶质母细胞瘤或TMZ耐药(LN-229Res和D54Res)胶质母细胞瘤的存活率，并用Macitentan和/或TMZ治疗。每周用生物发光成像监测肿瘤负荷。通过免疫荧光显微镜评估治疗对细胞分裂、细胞凋亡、肿瘤相关血管和与细胞存活相关的途径的影响。只有双重内皮素受体拮抗剂取消了星形胶质细胞和脑内皮细胞对TMZ对胶质瘤细胞的保护作用。在五项独立的生存研究中，包括耐药的胶质母细胞瘤，48只服用马西坦加替马西平的小鼠中有46只(96%)没有疾病的证据(P<；0.0001)，而其他组的小鼠全部死亡。在另一项分析中，在其他组小鼠死亡后，16只小鼠停止了Macitentan加TMZ的治疗。16只小鼠中只有3只最终发展为复发疾病，其中2只对额外的Macitentan加TMZ周期有反应。Macitentan下调了胶质瘤细胞和相关内皮细胞中与细胞分裂和生存相关的蛋白，从而增强了它们对TMZ的敏感性。Macitentan联合TMZ耐受性好，产生持久的反应，值得对胶质母细胞瘤患者进行临床评估。
The objective of the study was to determine whether astrocytes and brain endothelial cells protect glioma cells from temozolomide (TMZ) through an endothelin-dependent signaling mechanism and to examine the therapeutic efficacy of the dual endothelin receptor antagonist, macitentan, in orthotopic models of human glioblastoma. We evaluated several endothelin receptor antagonists for their ability to inhibit astrocyte- and brain endothelial cell-induced protection of glioma cells from TMZ in chemoprotection assays. We compared survival in nude mice bearing orthotopically implanted LN-229 glioblastomas or TMZ-resistant (LN-229Res and D54Res) glioblastomas that were treated with macitentan, TMZ, or both. Tumor burden was monitored weekly with bioluminescence imaging. The effect of therapy on cell division, apoptosis, tumor-associated vasculature, and pathways associated with cell survival was assessed by immunofluorescent microscopy. Only dual endothelin receptor antagonism abolished astrocyte- and brain endothelial cell-mediated protection of glioma cells from TMZ. In five independent survival studies, including TMZ-resistant glioblastomas, 46 of 48 (96%) mice treated with macitentan plus TMZ had no evidence of disease (P<0.0001), whereas all mice in other groups died. In another analysis, macitentan plus TMZ therapy was stopped in 16 mice after other groups had died. Only 3 of 16 mice eventually developed recurrent disease, 2 of which responded to additional cycles of macitentan plus TMZ. Macitentan downregulated proteins associated with cell division and survival in glioma cells and associated endothelial cells, which enhanced their sensitivity to TMZ. Macitentan plus TMZ are well tolerated, produce durable responses, and warrant clinical evaluation in glioblastoma patients.