Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Clin Cancer Res. 2013 Feb 15;19(4):938-48. doi: 10.1158/1078-0432.CCR-12-1722. Epub 2013 Jan 3.
The cytidine analogs 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase 1 (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application.
Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity, and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated patients with MDS (n = 90) and cytarabine-treated patients with acute myeloid leukemia (AML) (n = 76).
By high-performance liquid chromatography (HPLC), plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females than in males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared with high S-phase fraction disease (e.g., MDS vs. AML), because in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female patients with MDS treated with 5-azacytidine/decitabine.
Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.
用于治疗骨髓增生异常综合征（MDS）的胞嘧啶类似物 5-氮杂胞苷和地西他滨会产生一种分子表观遗传效应，即耗尽 DNA-甲基转移酶 1（DNMT1）。这种作用依赖于 S 期。因此，降低这些药物半衰期的遗传因素可能会影响疗效。记录这种影响，并阐明潜在机制，可能会导致临床应用的改善。
胞苷脱氨酶（CDA）可迅速使 5-氮杂胞苷/地西他滨失活。在小鼠和人类中，研究了 CDA SNP A79C 和性别对 CDA 表达、酶活性和药物药代动力学/药效学的影响，并在接受 5-氮杂胞苷/地西他滨治疗的 MDS 患者（n=90）和接受阿糖胞苷治疗的 AML 患者（n=76）中评估了对总生存期（OS）的影响。
通过高效液相色谱法（HPLC），如预期的那样，具有 SNP A79C 的个体的血浆 CDA 活性降低。有趣的是，女性的降低幅度甚至比男性更大。解释这种下降，与雄性相比，雌性小鼠的肝脏 CDA 表达明显降低。如预期的那样，通过质谱法测量的地西他滨血浆水平在女性中明显更高。在数学建模中，药物半衰期较短（例如，在男性中）的不利影响在低 S 期分数疾病（例如，MDS 与 AML）中比在高 S 期分数疾病中更大，因为在高 S 期分数疾病中，即使短暂暴露也会治疗大部分细胞。因此，在多变量分析中，接受 5-氮杂胞苷/地西他滨治疗的 MDS 男性患者的 OS 明显差于女性患者。
雄性中 CDA 表达/活性的增加导致胞嘧啶类似物半衰期缩短，可能导致 5-氮杂胞苷或地西他滨治疗效果更差。
