TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies.
TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies.
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DOI：
10.1016/j.ejphar.2009.06.066
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发表时间：
2009-12-25
影响因子：
5
通讯作者：
Griffith, Thomas S.
中科院分区：
文献类型：
--
作者：
Holoch, Peter A.;Griffith, Thomas S.
关键词：
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是肿瘤坏死因子超家族的成员，自1995年被发现以来，由于其在诱导恶性肿瘤细胞凋亡的同时不损伤正常细胞而受到广泛关注。因此，从诱导死亡的TRAIL受体激活凋亡信号通路提供了一种有吸引力的生物靶向癌症治疗方法。大量的研究集中在破译TRAIL受体信号级联和该途径的细胞内调节，因为许多人肿瘤细胞具有对TRAIL诱导的细胞凋亡的抗性机制。本文综述了目前关于TRAIL信号传导和抗性的知识状况，针对TRAIL受体和途径调节剂的治疗的临床前开发，以及从这一知识基础中出现的癌症治疗临床试验结果。基于TRAIL的癌症治疗方法从系统性施用重组可溶性TRAIL蛋白，与或不与传统化疗、放射或新型抗癌剂组合，到针对功能性TRAIL受体的激动性单克隆抗体，到TRAIL基因转移治疗。更好地理解TRAIL抗性机制可能允许开发利用这种细胞介导的凋亡途径的更有效的疗法。
Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor super family, has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. Consequently, activation of the apoptotic signaling pathway from the death-inducing TRAIL receptors provides an attractive, biologically-targeted approach to cancer therapy. A great deal of research has focused on deciphering the TRAIL receptor signaling cascade and intracellular regulation of this pathway, as many human tumor cells possess mechanisms of resistance to TRAIL-induced apoptosis. This review focuses on the currently state of knowledge regarding TRAIL signaling and resistance, the preclinical development of therapies targeted at TRAIL receptors and modulators of the pathway, and the results of clinical trials for cancer treatment that have emerged from this base of knowledge. TRAIL-based approaches to cancer therapy vary from systemic administration of recombinant, soluble TRAIL protein with or without the combination of traditional chemotherapy, radiation or novel anticancer agents to agonistic monoclonal antibodies directed against functional TRAIL receptors to TRAIL gene transfer therapy. A better understanding of TRAIL resistance mechanisms may allow for the development of more effective therapies that exploit this cell-mediated pathway to apoptosis.
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