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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 7; pp. 3928 - 3935
• Main Authors: GIOVANNETTI, Elisa, DEL TACCA, Mario, IANNOPOLLO, Mauro, BEVILACQUA, Generoso, MOSCA, Franco, DANESI, Romano, MEY, Valentina, FUND, Niccola, NANNIZZI, Sara, RICCI, Sergio, ORLANDINI, Cinzia, BOGGI, Ugo, CAMPANI, Daniela, DEL CHIARO, Marco
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-04-2006
• Subjects: 5'-Nucleotidase - biosynthesis; 5'-Nucleotidase - genetics; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cytidine Deaminase - biosynthesis; Cytidine Deaminase - genetics; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Deoxycytidine Kinase - biosynthesis; Deoxycytidine Kinase - genetics; Equilibrative Nucleoside Transporter 1 - biosynthesis; Equilibrative Nucleoside Transporter 1 - genetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Middle Aged; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pharmacology. Drug treatments; Predictive Value of Tests; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleoside Diphosphate Reductase - biosynthesis; Ribonucleoside Diphosphate Reductase - genetics; Transcriptional Activation; Treatment Outcome; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Tumors; Antineoplastic agent; Human; Gemcitabine; Transcription; Malignant tumor; Survival; Treatment; Antimetabolic; Pancreas cancer; Digestive diseases; Pyrimidine derivatives; Nucleoside; Fluorine Organic compounds; Predictive factor; Pyrimidine nucleoside; Carrier protein; Pancreatic disease
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-4203

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% CI), 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.