Levels of Gemcitabine Transport and Metabolism Proteins Predict Survival Times of Patients Treated With Gemcitabine for Pancreatic Adenocarcinoma
Levels of Gemcitabine Transport and Metabolism Proteins Predict Survival Times of Patients Treated With Gemcitabine for Pancreatic Adenocarcinoma
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DOI：
10.1053/j.gastro.2012.06.006
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发表时间：
2012-09-01
期刊：
影响因子：
29.4
通讯作者：
Van Laethem, Jean-Luc
中科院分区：
文献类型：
--
作者：
Marechal, Raphael;Bachet, Jean-Baptiste;Van Laethem, Jean-Luc
背景与目的：接受胰腺导管腺癌（PDAC）手术的患者经常接受吉西他滨辅助化疗。吉西他滨细胞毒性的关键决定因素包括人平衡型核苷转运蛋白1（hENT 1）、脱氧胞苷激酶（dCK）和核糖核苷酸还原酶亚基1（RRM 1）的活性。我们研究了这些蛋白质的肿瘤水平是否与手术后吉西他滨治疗的疗效相关。方法：从5个中心的434例患者中回顾性收集了切除PDAC的连续样本; 142例患者未接受辅助治疗（33%），243例接受基于吉西他滨的辅助治疗方案（56%），49例接受非吉西他滨治疗方案（11%）。我们用组织微阵列半定量免疫组织化学方法测定hENT 1、dCK和RRM 1的蛋白水平，并研究它们与患者总生存时间的关系。结果：患者中位生存期为32.0个月。在未接受辅助治疗的患者中，hENT 1、RRM 1和dCK水平与生存时间无关。在接受吉西他滨治疗的患者中，高水平的hENT 1和dCK与较长的生存时间显著相关（风险比分别为0.34 [P < .0001]和0.57 [P = .012]）。吉西他滨给药与hENT 1和dCK状态的相互作用检验具有统计学显著性（分别为P = .0007和P = .016）。在对该人群的多变量分析中，hENT 1和dCK保留了独立的预测值，并且每种蛋白质水平高的患者在吉西他滨辅助治疗后的生存时间最长。结论：PDAC中高水平的hENT 1和dCK预测辅助吉西他滨治疗患者的生存时间较长。
BACKGROUND & AIMS: Patients who undergo surgery for pancreatic ductal adenocarcinoma (PDAC) frequently receive adjuvant gemcitabine chemotherapy. Key determinants of gemcitabine cytotoxicity include the activities of the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit 1 (RRM1). We investigated whether tumor levels of these proteins were associated with efficacy of gemcitabine therapy following surgery. METHODS: Sequential samples of resected PDACs were retrospectively collected from 434 patients at 5 centers; 142 patients did not receive adjuvant treatment (33%), 243 received adjuvant gemcitabine-based regimens (56%), and 49 received nongemcitabine regimens (11%). We measured protein levels of hENT1, dCK, and RRM1 by semiquantitative immunohistochemistry with tissue microarrays and investigated their relationship with patients' overall survival time. RESULTS: The median overall survival time of patients was 32.0 months. Among patients who did not receive adjuvant treatment, levels of hENT1, RRM1, and dCK were not associated with survival time. Among patients who received gemcitabine, high levels of hENT1 and dCK were significantly associated with longer survival time (hazard ratios of 0.34 [P < .0001] and 0.57 [P = .012], respectively). Interaction tests for gemcitabine administration and hENT1 and dCK status were statistically significant (P = .0007 and P = .016, respectively). On multivariate analysis of this population, hENT1 and dCK retained independent predictive values, and those patients with high levels of each protein had the longest survival times following adjuvant therapy with gemcitabine. CONCLUSIONS: High levels of hENT1 and dCK in PDAC predict longer survival times in patients treated with adjuvant gemcitabine.