Institute of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Germany.
Pharmacogenomics. 2011 Apr;12(4):503-14. doi: 10.2217/pgs.10.200.
To adopt an individualized approach to assess cytarabine (ara-C) hematotoxicity, we studied the relationship between pharmacogenetic variability in the cytidine deaminase gene (CDA) and ara-C toxicity in native peripheral blood mononuclear cells from 100 healthy volunteers.
MATERIALS & METHODS: Peripheral blood mononuclear cells were incubated for 48 h with 3 µM ara-C, and cell viability was analyzed by flow cytometry with and without the addition of an equilibrative nucleoside transporter transport inhibitor. CDA promoter and exonic variants were genotyped to derive haplotypes for the CDA gene.
Significant between-subject variability was observed in ara-C toxicity (21-fold with 40.1% coefficient of variation compared with 1.2-fold within-subject variability [9.6% coefficient of variation]). Inhibition of hENT1 reversed ara-C cytotoxicity. The linked CDA promoter variants -451C>T, -92A>G, -31Del and the exonic 79A>C variant were associated with ara-C toxicity (p < 0.05). CDA*2A haplotype was associated with ara-C toxicity (p = 0.03).
Genetic polymorphisms within CDA may be risk factors for ara-C-induced hematotoxicity. Original submitted 6 October 2010; Revision submitted 29 November 2010.
为了采用个体化方法评估阿糖胞苷（ara-C）的血液毒性，我们研究了 100 名健康志愿者的天然外周血单个核细胞中胞苷脱氨酶基因（CDA）的遗传变异性与 ara-C 毒性之间的关系。
将外周血单个核细胞在 3µM ara-C 中孵育 48 小时，并通过流式细胞术分析细胞活力，同时添加和不添加平衡核苷转运蛋白转运抑制剂。对 CDA 启动子和外显子变异进行基因分型，以获得 CDA 基因的单倍型。
观察到 ara-C 毒性存在显著的个体间变异性（与 1.2 倍的个体内变异性（9.6%的变异系数）相比，差异达 21 倍，变异系数为 40.1%）。抑制 hENT1 逆转了 ara-C 的细胞毒性。连锁的 CDA 启动子变异 -451C>T、-92A>G、-31Del 和外显子 79A>C 变异与 ara-C 毒性相关（p<0.05）。CDA*2A 单倍型与 ara-C 毒性相关（p=0.03）。
CDA 内的遗传多态性可能是 ara-C 诱导的血液毒性的危险因素。原始提交日期为 2010 年 10 月 6 日；修订提交日期为 2010 年 11 月 29 日。
