A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers.
A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers.
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DOI：
10.1186/s13148-016-0237-y
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发表时间：
2016
影响因子：
5.7
通讯作者：
Götze KS
中科院分区：
文献类型：
--
作者：
Diesch J;Zwick A;Garz AK;Palau A;Buschbeck M;Götze KS
氮杂核苷阿扎胞苷和地西他滨目前用于治疗急性髓性白血病（AML）和骨髓增生异常综合征（MDS）的患者，不仅适合强化化疗，而且正在探索其他血液和实体癌。基于它们干扰DNA甲基化机制的能力，这些药物也被称为低甲基化剂（HMA）。由于DNA甲基化有助于表观遗传调控，氮杂核苷被进一步认为是第一批真正的“表观遗传药物”，已达到临床应用。然而，有趣的新证据表明，DNA低甲基化并不是这些药物的唯一作用机制。本文综述了10多年来氮杂核苷类药物的临床应用经验，并讨论了它们的分子作用，包括与DNA甲基化无关的几种作用。一个特别的重点是放在可能的原因，主要和获得性耐药氮杂核苷治疗。我们强调了目前氮杂核苷为基础的治疗的成功和持久性的局限性，并说明了更好地了解药物反应的分子决定因素具有克服耐药性的巨大潜力。
The azanucleosides azacitidine and decitabine are currently used for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients not only eligible for intensive chemotherapy but are also being explored in other hematologic and solid cancers. Based on their capacity to interfere with the DNA methylation machinery, these drugs are also referred to as hypomethylating agents (HMAs). As DNA methylation contributes to epigenetic regulation, azanucleosides are further considered to be among the first true “epigenetic drugs” that have reached clinical application. However, intriguing new evidence suggests that DNA hypomethylation is not the only mechanism of action for these drugs. This review summarizes the experience from more than 10 years of clinical practice with azanucleosides and discusses their molecular actions, including several not related to DNA methylation. A particular focus is placed on possible causes of primary and acquired resistances to azanucleoside treatment. We highlight current limitations for the success and durability of azanucleoside-based therapy and illustrate that a better understanding of the molecular determinants of drug response holds great potential to overcome resistance.