Momparler Richard L
Centre de recherche, Hôpital Sainte-Justine, Montreal, Quebec, Canada.
Semin Hematol. 2005 Jul;42(3 Suppl 2):S9-16. doi: 10.1053/j.seminhematol.2005.05.002.
The preclinical pharmacology of 5-aza-2'-deoxycytidine (decitabine, 5AZA-CdR) is reviewed. 5AZA-CdR, an analogue of deoxycytidine, is a prodrug that requires metabolic activation by deoxycytidine kinase. The active inhibitor in the cell is its triphosphate form (5AZA-dCTP), which incorporates very readily into DNA to produce an inhibition of DNA methyltransferase. The mechanism responsible for the antileukemic action of 5AZA-CdR is related to its reversal of epigenetic silencing by aberrant DNA methylation of genes that suppress leukemiogenesis. 5AZA-CdR is an S-phase-specific agent. At concentrations in the range of micromolars this analogue can induce terminal differentiation and loss of clonogenicity of human leukemic cells. Drug resistance to 5AZA-CdR occurs primarily by reduction in deoxycytidine kinase activity or increase in the activity of cytidine deaminase, the enzyme that inactivates this analogue. 5AZA-CdR is a very potent antileukemic agent in animal models, more effective than the related antileukemic drug, cytosine arabinoside. In humans, 5AZA-CdR has a short half-life of 15 to 25 minutes due to rapid inactivation by liver cytidine deaminase. The major toxicity produced by 5AZA-CdR is myelosuppression. Preliminary clinical studies in patients with hematologic malignancies indicate that 5AZA-CdR is an active chemotherapeutic agent. The optimal dose-schedule for this interesting epigenetic agent with a novel mechanism of action remains to be determined. Translation of the pharmacology of 5AZA-CdR into therapeutic regimens based on scientific rationale can be used to obtain this objective.
本文综述了5-氮杂-2'-脱氧胞苷（地西他滨，5AZA-CdR）的临床前药理学。5AZA-CdR是脱氧胞苷的类似物，是一种前体药物，需要通过脱氧胞苷激酶进行代谢激活。细胞中的活性抑制剂是其三磷酸形式（5AZA-dCTP），它很容易掺入DNA中，从而抑制DNA甲基转移酶。5AZA-CdR抗白血病作用的机制与其通过抑制白血病发生的基因异常DNA甲基化逆转表观遗传沉默有关。5AZA-CdR是一种S期特异性药物。在微摩尔浓度范围内，这种类似物可诱导人白血病细胞终末分化并丧失克隆形成能力。对5AZA-CdR的耐药性主要通过脱氧胞苷激酶活性降低或胞苷脱氨酶活性增加而产生，胞苷脱氨酶是使这种类似物失活的酶。在动物模型中，5AZA-CdR是一种非常有效的抗白血病药物，比相关的抗白血病药物阿糖胞苷更有效。在人类中，由于肝脏胞苷脱氨酶的快速失活，5AZA-CdR的半衰期很短，为15至25分钟。5AZA-CdR产生的主要毒性是骨髓抑制。对血液系统恶性肿瘤患者的初步临床研究表明，5AZA-CdR是一种有效的化疗药物。这种具有新型作用机制的有趣的表观遗传药物的最佳剂量方案仍有待确定。将5AZA-CdR的药理学转化为基于科学原理的治疗方案可用于实现这一目标。
