NYU Clinical Cancer Center, 160 East 34th Street, New York, NY 10016, USA.
Invest New Drugs. 2010 Dec;28 Suppl 1(Suppl 1):S58-78. doi: 10.1007/s10637-010-9591-3. Epub 2010 Dec 4.
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.
组蛋白去乙酰化酶抑制剂（HDACI）作为治疗特定类型非霍奇金淋巴瘤（NHL）的最有希望的新药之一正在兴起。它们在 T 细胞淋巴瘤、可能的霍奇金淋巴瘤和惰性 B 细胞淋巴瘤中特别活跃。目前，这两种药物，伏立诺他和罗米地辛，已被美国批准用于治疗复发性和难治性皮肤 T 细胞淋巴瘤（CTCL）。最初，这些药物的开发理念是通过调节染色质的凝聚和解凝聚来影响转录激活和基因表达。现在很清楚，它们的作用不仅仅局限于染色质，通过影响组蛋白和其他细胞内蛋白质的乙酰化状态，它们通过多种途径改变基因表达和细胞功能。基因表达谱和功能遗传分析进一步了解了这些药物影响的各种分子途径，包括细胞周期调节、细胞增殖、凋亡和血管生成途径，这些途径在淋巴瘤的发生中都很重要。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，这可能解释了这些药物在 T 细胞淋巴瘤和霍奇金淋巴瘤中的高活性。在淋巴瘤中存在大量的表观遗传失调证据，这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 抑制剂根据其化学结构至少可以分为四类。目前，这些 HDAC 抑制剂中的几种正在进行临床试验，无论是作为单一药物还是与化疗或其他生物制剂联合使用。它们易于给药，通常具有良好的耐受性，副作用最小。不同的剂量水平和方案以及使用等特异性 HDAC 抑制剂是正在采用的一些策略，旨在提高这些药物在治疗淋巴瘤中的治疗效果。也可能存在类别的差异，转化为对不同淋巴瘤的特定活性。HDAC 抑制剂很可能被纳入针对淋巴瘤的靶向治疗联合方案中，无论是在初始治疗还是复发治疗中。
