Targeting epigenetic abnormalities with histone deacetylase inhibitors
Targeting epigenetic abnormalities with histone deacetylase inhibitors
复制标题
DOI：
10.1002/cncr.22064
复制
发表时间：
2006-08-15
期刊：
影响因子：
6.2
通讯作者：
Kummar, Shivaani
中科院分区：
文献类型：
--
作者：
Conley, Barbara A.;Wright, John J.;Kummar, Shivaani
背景。染色体结构的改变在基因转录的控制中发挥着关键作用。这些“表观遗传”改变包括通过乙酰化和/或磷酸化对组蛋白和其他蛋白质进行修饰。通常，这些修饰在正常组织中是很好平衡的并且是高度可逆的，但它们在肿瘤细胞中可能是不平衡的并且是可遗传的。组蛋白脱乙酰酶抑制剂增加组蛋白乙酰化，从而以协调的方式调节一部分基因的表达。在散发性癌症中，一些与恶性表型相关的肿瘤抑制基因受到表观遗传机制的抑制。因此，用组蛋白脱乙酰酶抑制剂治疗可能会改变肿瘤表型以抑制此类肿瘤的生长。作者回顾了组蛋白脱乙酰酶抑制剂作为潜在抗癌药物的基本原理，并回顾了各类组蛋白脱乙酰酶抑制剂的一些临床前和早期临床试验数据。 结果。已观察到临床前和临床抗肿瘤活性。毒性包括疲劳、骨髓抑制和心脏异常。结论。组蛋白脱乙酰酶抑制剂在一些实体瘤和血液恶性肿瘤中显示出有希望的活性。
BACKGROUND. Alterations in chromosome structure play critical roles in the control of gene transcription. These "epigenetic" alterations include modification of histones and other proteins by acetylation and/or phosphorylation. Normally, these modifications are balanced finely and are highly reversible in normal tissues, but they may be imbalanced and heritable in tumor cells. Histone deacetylase inhibitors increase histone acetylation, thereby modulating the expression of a subset of genes in a coordinated fashion. Several tumor suppressor genes associated with the malignant phenotype are repressed by epigenetic mechanisms in sporadic cancers. Thus, therapy with histone deacetylase inhibitors may alter tumor phenotype to inhibit growth in such tumors.METHODS. The authors reviewed the rationale for histone deacetylase inhibitors as potential anticancer agents and reviewed some preclinical and early clinical trial data with various classes of histone deacetylase inhibitors.RESULTS. Preclinical and clinical antitumor activity has been observed. Toxicities include fatigue, myelosuppression, and cardiac abnormalities.CONCLUSIONS. Histone deacetylase inhibitors have shown promising activity in some solid tumors and hematologic malignancies.