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首页> 外文期刊>Chemotherapy Research and Practice >Development of an Oral Form of Azacytidine:2′3′5′Triacetyl-5-Azacytidine
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Development of an Oral Form of Azacytidine:2′3′5′Triacetyl-5-Azacytidine

机译：口服氮杂胞苷：2′3′5′三乙酰基-5-氮杂胞苷的研制

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Myelodysplastic syndromes (MDSs) represent a group of incurable stem-cell malignancies which are predominantly treated by supportive care. Epigenetic silencing through promoter methylation of a number of genes is present in poor-risk subtypes of MDS and often predicts transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine, two FDA-approved DNA methyltransferase (DNMT) inhibitors, are able to improve overall response although their oral bioavailability complicates their clinical use. This study evaluated2′,3′,5′-triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation.
机译：骨髓增生异常综合症（MDS）代表了一组无法治愈的干细胞恶性肿瘤，主要通过支持治疗进行治疗。在MDS的低风险亚型中，存在通过许多基因的启动子甲基化引起的表观遗传沉默，并且经常预测会转化为急性骨髓性白血病（AML）。尽管两种药物的口服生物利用度使它们的临床应用复杂化，但阿扎胞苷和地西他滨是两种FDA批准的DNA甲基转移酶（DNMT）抑制剂，能够改善总体反应。这项研究评估了2'，3'，5'-三乙酰基5-阿扎胞苷（TAC）作为阿扎胞苷的潜在前药。与前体化合物相比，前药在生物利用度，溶解度和稳定性方面显示出显着的药代动力学改善。体内分析表明缺乏一般毒性以及存活率显着提高。药效学分析证实了其在体内抑制总体甲基化的能力。这些数据表明酯化的核苷衍生物可能是阿扎胞苷的有效前药，并鼓励进一步研究TAC的代谢，活性和可能的​​临床评估。

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