Rein Lindsay A M, Rizzieri David A
Duke University Medical Center - Medicine, Durham, NC, USA.
Duke University Medical Center - Medicine, 1149 North Pavilion Duke University Durham, NC 27710, USA.
Ther Adv Hematol. 2014 Dec;5(6):211-20. doi: 10.1177/2040620714552615.
Acute myeloid leukemia (AML) has been treated for over four decades with standard induction chemotherapy including seven days of cytosine arabinoside (cytarabine, ara-C) infusion. Cytarabine, while effective in killing leukemic cells, is subject to development of several resistance mechanisms rendering the drug ineffective in many patients. Elacytarabine, a lipophilic 5'-elaidic acid ester or nucleoside analogue of cytosine arabinoside, was created with the intent of overcoming resistance mechanisms including reduced expression of the human equilibrative nucleoside transporter 1 (hENT1) required for cytarabine entry into cells, as well as increased activity of cytidine deaminase (CDA) which breaks down the active metabolite of cytarabine, ara-CTP. Elacytarabine enters cells independently of transporters, has a longer half life compared with cytarabine and is not subject to deactivation by CDA. Preclinical data were encouraging although subsequent clinical studies have failed to show superiority of elacytarabine compared with standard of care as monotherapy in patients with AML. Clinical trials utilizing elacytarabine in combination with anthracyclines are ongoing. Use of hENT1 expression as a predictive marker for cytarabine or elacytarabine response has been studied with no conclusive validation to date. Despite promising early results, the jury is still out in regards to this novel agent as an effective alternative to standard cytarabine therapy in acute leukemias, especially in combination with additional agents such as anthracyclines.
急性髓系白血病（AML）采用标准诱导化疗进行治疗已超过四十年，包括连续七天输注阿糖胞苷（胞嘧啶阿拉伯糖苷，阿糖胞苷）。阿糖胞苷虽然在杀死白血病细胞方面有效，但会产生多种耐药机制，导致该药物在许多患者中无效。依拉阿糖胞苷是一种亲脂性的5'-反油酸酯或阿糖胞苷的核苷类似物，其研发目的是克服耐药机制，包括降低阿糖胞苷进入细胞所需的人平衡核苷转运体1（hENT1）的表达，以及增加胞苷脱氨酶（CDA）的活性，该酶会分解阿糖胞苷的活性代谢产物阿糖胞苷三磷酸（ara-CTP）。依拉阿糖胞苷独立于转运体进入细胞，与阿糖胞苷相比半衰期更长，且不会被CDA失活。临床前数据令人鼓舞，尽管随后的临床研究未能显示依拉阿糖胞苷在AML患者中作为单药治疗与标准治疗相比具有优越性。使用依拉阿糖胞苷联合蒽环类药物的临床试验正在进行。目前已经研究了将hENT1表达作为阿糖胞苷或依拉阿糖胞苷反应的预测标志物，但迄今为止尚无确凿的验证。尽管早期结果令人鼓舞，但对于这种新型药物作为急性白血病标准阿糖胞苷治疗的有效替代方案，尤其是与蒽环类药物等其他药物联合使用时，仍有待进一步确定。
