PDF(Pubmed)
Abstract：
Decitabine, a member of the 5-azanucleosides, has a dose-dependent mechanism of action in vitro: termination of DNA replication at high doses, and inhibition of DNA methyltransferase at low doses. The alteration of DNA methylation patterns by low-dose decitabine is hypothesized to upregulate genes, which promote myeloblast differentiation. In a phase III clinical trial, low-dose decitabine achieved a superior overall response rate (ORR) when compared with \'treatment choice\' [consisting of low-dose cytarabine (80%) and supportive care (20%)] as a frontline treatment for elderly patients with acute myeloid leukemia (AML). Despite an improved ORR, the median overall survival (OS) for elderly patients with AML was poor, <1 year. In turn, venetoclax was added to low-dose decitabine, the combination of which significantly improved the ORR and median OS in elderly patients with AML. Currently, hypomethylating agents are being combined with other novel therapies as investigational strategies for elderly and unfit patients with AML. They are also being evaluated as components of maintenance therapy in patients achieving remission. An oral formulation of decitabine has been developed which relies on the concomitant use of oral cedazuridine to protect against first pass metabolism. This oral formulation, which has been approved in myelodysplastic syndrome, is intended to increase convenience of use and therefore compliance in patients. This review characterizes the evolution of decitabine, its oral formulation, and its future in the treatment of AML.
摘要：
地西他滨,5-氮杂核苷的成员，在体外具有剂量依赖性的作用机制：高剂量时终止DNA复制，和抑制低剂量的DNA甲基转移酶。低剂量地西他滨对DNA甲基化模式的改变被假设为上调基因，促进成髓细胞分化。在一项III期临床试验中,低剂量地西他滨作为老年急性髓细胞性白血病(AML)患者的一线治疗,与''治疗选择''[包括低剂量阿糖胞苷(80%)和支持治疗(20%)]相比,获得了更高的总体缓解率(ORR).尽管ORR有所改善，老年AML患者的中位总生存期（OS）较差，<1年。反过来,维奈托克被添加到低剂量的地西他滨，联合用药可显著改善老年AML患者的ORR和中位OS.目前,低甲基化药物正与其他新疗法联合作为老年和不适合AML患者的研究策略。它们也被评估为实现缓解的患者的维持治疗的组成部分。已经开发了地西他滨的口服制剂,其依赖于伴随使用口服西达尿苷来防止首过代谢。这种口服制剂，已被批准用于骨髓增生异常综合征，旨在提高使用的便利性，从而提高患者的依从性。这篇综述描述了地西他滨的演变，其口服制剂，以及其在治疗AML方面的未来。
