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.
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.
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男性中 CDA 表达/活性增加会导致胞苷类似物半衰期缩短，并可能导致 5-氮杂胞苷或地西他滨治疗的结果更差。
DOI：
10.1158/1078-0432.ccr-12-1722
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发表时间：
2013-02-15
期刊：
影响因子：
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通讯作者：
Saunthararajah Y
中科院分区：
文献类型：
--
作者：
Mahfouz RZ;Jankowska A;Ebrahem Q;Gu X;Visconte V;Tabarroki A;Terse P;Covey J;Chan K;Ling Y;Engelke KJ;Sekeres MA;Tiu R;Maciejewski J;Radivoyevitch T;Saunthararajah Y
The cytidine analogues 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase (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 MDS patients (n=90) and cytarabine-treated acute myeloid leukemia (AML) patients (n=76). By 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 compared to 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 to high S-phase fraction disease (e.g., MDS versus AML), since 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 MDS patients treated with 5-azacytidine/decitabine. Increased CDA expression/activity in males contributes to decreased cytidine analogue half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.
