Christian Medical College, Vellore 632004, India.
Pharmacogenomics. 2012 Feb;13(3):269-82. doi: 10.2217/pgs.11.149.
Cytidine deaminase (CDA) irreversibly deaminates cytarabine (Ara-C), a key component of acute myeloid leukemia (AML) induction and consolidation therapy. CDA overexpression results in Ara-C resistance, while decreased expression is associated with toxicity. We evaluated factors influencing variation in CDA mRNA expression in adult AML patients and normal controls, and how they contributed to Ara-C cytotoxicity in AML cells.
MATERIALS & METHODS: CDA mRNA expression in 100 de novo AML patients and 36 normal controls were determined using quantitative reverse-transcriptase PCR. Genetic variants in the CDA gene were screened by direct sequencing. IC₅₀ of Ara-C was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
CDA RNA expression as well as Ara-C IC₅₀ showed wide variation in AML samples and normal controls. Fourteen sequence variants were identified, three of which (-33delC, intron 2 TCAT repeat and the 3´untranslated region 816delC variants) showed significant association with RNA expression and the nonsynonymous coding variant 79A>C was associated with Ara-C cytotoxicity.
CDA genetic variants explain the variation in RNA expression and may be candidates for individualizing Ara-C therapy.
胞苷脱氨酶（CDA）可使阿糖胞苷（Ara-C）不可逆脱氨，后者是急性髓系白血病（AML）诱导和巩固治疗的关键组成部分。CDA 过表达导致 Ara-C 耐药，而表达降低与毒性相关。我们评估了影响成人 AML 患者和正常对照者 CDA mRNA 表达变化的因素，以及它们如何影响 AML 细胞中 Ara-C 的细胞毒性。
采用定量逆转录-PCR 法测定 100 例初治 AML 患者和 36 例正常对照者的 CDA mRNA 表达。通过直接测序筛选 CDA 基因中的遗传变异。采用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐法测定 Ara-C 的 IC₅₀。
AML 样本和正常对照者的 CDA RNA 表达及 Ara-C IC₅₀ 均存在广泛的变异性。共鉴定出 14 种序列变异，其中 3 种（-33delC、内含子 2 TCAT 重复和 3´非翻译区 816delC 变异）与 RNA 表达显著相关，而非同义编码变异 79A>C 与 Ara-C 细胞毒性相关。
CDA 遗传变异可解释 RNA 表达的变化，可能是 Ara-C 个体化治疗的候选因素。
