Targeting histone deacetyalses in the treatment of B- and T-cell malignancies.
Targeting histone deacetyalses in the treatment of B- and T-cell malignancies.
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DOI：
10.1007/s10637-010-9591-3
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发表时间：
2010-12
影响因子：
3.4
通讯作者：
O'Connor, Owen A.
中科院分区：
文献类型：
--
作者：
Zain, Jasmine;O'Connor, Owen A.
HDAC抑制剂（HDACI）现在正在成为治疗选择形式的非霍奇金淋巴瘤（NHL）的最有前途的新药物类别之一。它们在T细胞淋巴瘤，可能是霍奇金淋巴瘤和惰性B细胞淋巴瘤中特别活跃。目前，其中两种药物伏立诺他和罗米地辛已在美国获批用于治疗复发性和难治性皮肤T细胞淋巴瘤（CTCL）。最初，开发这些试剂的想法是，它们通过调节染色质凝聚和解凝聚来影响转录激活，从而影响基因表达。现在很清楚，它们的作用超越了染色质，通过影响组蛋白和其他细胞内蛋白的乙酰化状态，它们通过多种途径修饰基因表达和细胞功能。基因表达谱和功能遗传学分析已经导致了对受这些试剂影响的各种分子途径的进一步理解，包括细胞周期调节、细胞增殖途径、细胞凋亡和血管生成，所有这些在淋巴瘤发生中都是重要的。也有越来越多的数据支持这些药物对T细胞受体和免疫功能的影响，这可以解释这些药物在T细胞淋巴瘤和霍奇金淋巴瘤中的高水平活性。有充分的证据表明，淋巴瘤的表观遗传失调可能是这些药物作用机制的基础，但这些药物如何发挥作用仍不清楚。目前的HDAC抑制剂可以根据其化学结构分为至少四类。目前，这些HDAC抑制剂中的几种作为单一药剂以及与化学疗法或其它生物药剂组合在临床试验中。它们易于管理，通常耐受性良好，副作用最小。不同的剂量水平和时间表以及使用同种特异性HDAC抑制剂是用于增加这些药物在治疗淋巴瘤中的治疗效果的一些策略。也可能存在类别差异，转化为针对不同淋巴瘤的特异性活性。HDAC抑制剂可能会被纳入淋巴瘤的前期和复发背景下的靶向治疗组合中。
HDAC inhibitors (HDACI) are now emerging as one of the most promising new classes of drugs for the treatment of select forms of non-Hodgkin’s lymphoma (NHL). They are particularly active in T-cell lymphomas, possibly hodgkin’s lymphoma and indolent B cell lymphomas. Presently, two of these agents, vorinostat and romidepsin, have been approved in the US for the treatment of relapsed and refractory cutaneous T cell lymphomas (CTCL). Initially, these agents were developed with the idea that they affected transcriptional activation and thus gene expression, by modulating chromatin condensation and decondensation. It is now clear that their effects go beyond chromatin and by affecting the acetylation status of histones and other intra-cellular proteins, they modify gene expression and cellular function via multiple pathways. Gene expression profiles and functional genetic analysis has led to further understanding of the various molecular pathways that are affected by these agents including cell cycle regulation, pathways of cellular proliferation, apoptosis and angiogenesis all important in lymphomagenesis. There is also increasing data to support the effects of these agents on T cell receptor and immune function which may explain the high level of activity of these agents in T cell lymphomas and hodgkin’s lymphoma. There is ample evidence of epigenetic dysregulation in lymphomas which may underlie the mechanisms of action of these agents but how these agents work is still not clear. Current HDAC inhibitors can be divided into at least four classes based on their chemical structure. At present several of these HDAC inhibitors are in clinical trials both as single agents and in combination with chemotherapy or other biological agents. They are easy to administer and are generally well tolerated with minimal side effects. Different dosing levels and schedules and the use of isospecific HDAC inhibitors are some of the strategies that are being employed to increase the therapeutic effect of these agents in the treatment of lymphomas. There may also be class differences that translate into specific activity against different lymphoma. HDAC inhibitors will likely be incorporated into combinations of targeted therapies both in the upfront and relapsed setting for lymphomas.
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影响因子：
30.8
作者：
Bereshchenko, OR;Gu, W;Dalla-Favera, R
通讯作者：
Dalla-Favera, R
影响因子：
20.3
作者：
Buglio, Daniela;Georgakis, Georgios V.;Younes, Anas
通讯作者：
Younes, Anas
影响因子：
1.8
作者：
Campas-Moya, Clara
通讯作者：
Campas-Moya, Clara
影响因子：
11.5
作者：
Dai, Yun;Chen, Shuang;Grant, Steven
通讯作者：
Grant, Steven
影响因子：
16
作者：
Cohen, HY;Lavu, S;Sinclair, DA
通讯作者：
Sinclair, DA