Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine

被引:289
作者
Giovannetti, E
Del Tacca, M
Mey, V
Funel, N
Nannizzi, S
Ricci, S
Orlandini, C
Boggi, U
Campani, D
Del Chiaro, M
Iannopollo, M
Bevilacqua, G
Mosca, F
Danesi, R
机构
[1] Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, I-56126 Pisa, Italy
[2] Univ Pisa, Div Surg Mol & Ultrasound Pathol, I-56126 Pisa, Italy
[3] Univ Pisa, Div Gen Surg & Transplant, Dept Oncol Transplants & Adv Technol Med, I-56126 Pisa, Italy
[4] Univ Hosp, Div Med Oncol, Pisa, Italy
关键词
D O I
10.1158/0008-5472.CAN-05-4203
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Gene expression analysis may help the management of cancer patients, allowing the selection of subjects responding to treatment. The aim of this study was the characterization of expression pattern of genes involved in gemcitabine activity in pancreas tumor specimens and its correlation with treatment outcome. The role of drug transport and metabolism on gemcitabine cytotoxicity was examined with specific inhibitors, whereas transcription analysis of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-NT), cytidine deaminase (CDA), and ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2) was done by quantitative reverse transcription-PCR in tumor tissue isolated by laser microdissection from surgical or biopsy samples of 102 patients. Association between clinical outcome and gene expression levels was estimated using Kaplan-Meier method and Cox's proportional hazards model. Transport and metabolism had a key role on gemcitabine sensitivity in vitro; moreover, hENT1, dCK, 5'-NT, CDA, RRM1, and RRM2 were detectable in most tumor specimens. hENT1 expression was significantly correlated with clinical outcome. Patients with high levels of hENT1 had a significantly longer overall survival [median, 25.7; 95% confidence interval (95% Cl), 17.6-33.7 months in the higher expression tertile versus median, 8.5; 95% CI, 7.0-9.9 months in the lower expression tertile]. Similar results were obtained with disease-free survival and time to disease progression, and the multivariate analysis confirmed the prognostic significance of hENT1. This study suggests that the expression levels of hENT1 may allow the stratification of patients based on their likelihood of survival, thus offering a potential new tool for treatment optimization.
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页码:3928 / 3935
页数:8
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