Department of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Expert Opin Investig Drugs. 2013 Sep;22(9):1211-23. doi: 10.1517/13543784.2013.815165. Epub 2013 Jul 3.
Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agent targeting the epigenome, specifically chromatin remodelling, resulting in modulation of genes responsible for apoptosis and cell cycle regulation, and also hyperacetylation of many non-histone proteins. Panobinostat is a potent pan-histone inhibitor of HDAC enzymes implicated in cancer development and progression. Activity has been demonstrated in hematological diseases, such as cutaneous T-cell lymphoma (CTCL), Hodgkin lymphoma (HL), myeloma and myeloid malignancies.
We discuss basic pharmacology, followed by early phase trial results and analyse recent large Phase II trials in HL, CTCL, myeloid malignancies and Waldenstrom's macroglobulinemia (WM). Future directions for drug development including potential predictive biomarkers are considered.
The results of Phase II trials prove that oral panobinostat is deliverable with dosing regimens of three times per week, either weekly or biweekly. The major hematologic side-effect of myelosuppression, in particular thrombocytopenia, is transient and manageable, as are the non-hematologic side-effects. Encouraging responses are observed in HL, CTCL, myelofibrosis and WM. The safety and efficacy results from studies of combination therapy with azacitidine in acute myeloid leukemia and myelodysplastic syndromes suggest that this agent may find a place in the management of a range of hematologic cancers.
组蛋白去乙酰化酶抑制剂（HDACIs）是一类针对表观基因组的抗肿瘤药物，特别是染色质重塑，导致负责细胞凋亡和细胞周期调节的基因的调节，以及许多非组蛋白的过度乙酰化。帕比司他是一种有效的组蛋白泛抑制剂，涉及癌症的发生和发展。在血液系统疾病中已有活性，如皮肤 T 细胞淋巴瘤（CTCL）、霍奇金淋巴瘤（HL）、骨髓瘤和髓系恶性肿瘤。
我们讨论了基础药理学，然后分析了早期临床试验结果，并分析了 HL、CTCL、髓系恶性肿瘤和瓦尔登斯特伦巨球蛋白血症（WM）的最近大型 II 期试验。考虑了药物开发的未来方向，包括潜在的预测生物标志物。
II 期试验的结果证明，每周或每两周三次的每周一次的给药方案可实现口服帕比司他的给药。主要的血液学副作用骨髓抑制，特别是血小板减少，是短暂的且可管理的，非血液学副作用也是如此。在 HL、CTCL、骨髓纤维化和 WM 中观察到令人鼓舞的反应。在急性髓细胞白血病和骨髓增生异常综合征中与阿扎胞苷联合治疗的研究结果表明，该药物可能在一系列血液系统癌症的治疗中占有一席之地。
