Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications
Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications
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DOI：
10.1158/1078-0432.ccr-07-2114
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发表时间：
2007-12-15
影响因子：
11.5
通讯作者：
Richon, Victoria M.
中科院分区：
文献类型：
--
作者：
Fantin, Valeria R.;Richon, Victoria M.
组蛋白去乙酰酶抑制剂(HDI)是一种很有前途的治疗癌症的新方法。HDIs已被证明在各种转化的细胞系中诱导分化、细胞周期停滞和凋亡；在动物模型中抑制肿瘤生长；在临床试验中显示出抗肿瘤活性。伏立诺他在30%的晚期皮肤T细胞淋巴瘤患者中显示出类似的临床反应，是第一个被批准用于癌症治疗的HDI，目前正在评估其他适应症。更好地了解人类免疫缺陷病毒耐药的分子决定因素可能为提高临床疗效的联合治疗提供基础。对治疗的不良反应可能与系统性因素有关，如药代动力学或肿瘤特异性因素，在恶性肿瘤细胞(肿瘤固有的)或肿瘤微环境水平上都是如此。本文就肿瘤耐药的内在机制(不包括慢性接触引起的获得性耐药机制)作一综述。特别是，注意选定的机制，这些机制涉及人类发展倡议的化学类别，并有助于设计合理的组合战略。
Histone deacetylase inhibitors (HDI) are a promising new approach to the treatment of cancer. HDIs have been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of transformed cell lines; inhibit tumor growth in animal models; and show antitumor activity in clinical trials. Vorinostat, which has shown clinical responses in similar to 30% of patients with advanced cutaneous T-cell lymphoma, is the first HDI approved for the treatment of cancer, and it is currently being evaluated in other indications. A better understanding of the molecular determinants of resistance to HDIs may provide the basis for therapeutic combinations with improved clinical efficacy. Poor response to treatment could be linked to systemic factors like pharmacokinetics or to tumor-specific factors both at the level of the malignant cells (tumor intrinsic) or the tumor microenvironment. This review focuses on the tumor intrinsic mechanisms of drug resistance (excluding mechanism of acquired resistance due to chronic exposure). In particular, attention is given to selected mechanisms that are relevant across chemical classes of HDIs and that can aid in the design of rational combination strategies.