实体瘤患者血清胞苷脱氨酶活性个体间差异的决定因素。
Determinants of the interindividual variability in serum cytidine deaminase activity of patients with solid tumours.
机构信息
Department of Medical Oncology, Cochin Hospital, Paris Descartes University, CARPEM, AP-HP, Paris, France.
Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, CARPEM, AP-HP, Paris, France.
出版信息
Br J Clin Pharmacol. 2019 Jun;85(6):1227-1238. doi: 10.1111/bcp.13849. Epub 2019 Jan 30.
AIMS
Cytidine deaminase (CDA) activity in cancer patients' serum has been proposed as a predictive biomarker for efficacy and toxicity of nucleoside analogues. However, discrepant results about its predictive value have been reported due to the high interindividual variability in CDA activity. This study aimed at identifying determinants of this interindividual variability.
METHODS
From December 2014 to November 2015, 183 patients were prospectively included. Serum CDA activity, biological and clinical characteristics as well as five common single nucleotide polymorphisms (SNPs) in the CDA gene (c.-451C > T, c.-92A > G, c.-33_-31delC, c.79A > C, c.435 T > C) were analysed. Associations between clinical characteristics, pharmacogenetic variants and CDA activity were univariately tested. P < 0.1-candidate variables were analysed through a multivariate analysis. The association between CDA activity and toxicity was assessed for the 56 gemcitabine-treated patients. Intraindividual variability in CDA activity was explored in six pancreatic cancer patients treated with gemcitabine.
RESULTS
Median CDA activity was 3.97 U mg (range 1.53-15.49 U mg ). A univariate analysis showed that CDA activity was statistically associated with Eastern Cooperative Oncology Group performance status, mild or severe malnutrition, inflammatory syndrome, leucocyte count, neutrophil count, albumin, C-reactive protein and -c.-33_-31delC single nucleotide polymorphism. A multivariate analysis identified that only neutrophil count (P < 0.0001) and severe malnutrition (P = 0.0278) were independently associated with CDA activity. Low CDA activity (<2 U mg ) was not statistically associated with severe gemcitabine-related toxicities (P = 0.16). A decrease in CDA activity was observed during the longitudinal follow-up of six pancreatic cancer patients treated with gemcitabine (P = 0.03).
CONCLUSIONS
These results suggest that neutrophil count and malnutrition should be considered for the interpretation of pretherapeutic CDA activity.
目的
癌症患者血清中的胞苷脱氨酶（CDA）活性已被提议作为核苷类似物疗效和毒性的预测生物标志物。然而，由于 CDA 活性的个体间差异很大，因此关于其预测价值的结果存在差异。本研究旨在确定这种个体间差异的决定因素。
方法
从 2014 年 12 月至 2015 年 11 月，前瞻性纳入 183 例患者。分析血清 CDA 活性、生物学和临床特征以及 CDA 基因中的五个常见单核苷酸多态性（SNP）（c.-451C>T、c.-92A>G、c.-33_-31delC、c.79A>C、c.435T>C）。通过单变量分析测试临床特征、药物遗传学变异与 CDA 活性之间的关联。通过多变量分析分析 P<0.1-候选变量。评估 56 例接受吉西他滨治疗的患者的 CDA 活性与毒性之间的关联。在接受吉西他滨治疗的 6 例胰腺癌患者中探索了 CDA 活性的个体内变异性。
结果
中位 CDA 活性为 3.97 U·mg（范围 1.53-15.49 U·mg）。单变量分析显示，CDA 活性与东部合作肿瘤学组表现状态、轻度或重度营养不良、炎症综合征、白细胞计数、中性粒细胞计数、白蛋白、C 反应蛋白和 c.-33_-31delC 单核苷酸多态性有统计学关联。多变量分析确定只有中性粒细胞计数（P<0.0001）和重度营养不良（P=0.0278）与 CDA 活性独立相关。低 CDA 活性（<2 U·mg）与严重的吉西他滨相关毒性无统计学相关性（P=0.16）。对接受吉西他滨治疗的 6 例胰腺癌患者的纵向随访中观察到 CDA 活性降低（P=0.03）。
结论
这些结果表明，在解释治疗前 CDA 活性时，应考虑中性粒细胞计数和营养不良。
Zotero 插件