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

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.

[1]  M. Monden,et al.  Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma , 2004, Clinical Cancer Research.

[2]  W. Evans,et al.  Pharmacogenomics: unlocking the human genome for better drug therapy. , 2001, Annual review of pharmacology and toxicology.

[3]  D. Gandara,et al.  Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  L. Gelbert,et al.  An Increase in the Expression of Ribonucleotide Reductase Large Subunit 1 Is Associated with Gemcitabine Resistance in Non-Small Cell Lung Cancer Cell Lines , 2004, Cancer Research.

[5]  H. Pitt,et al.  Thymidylate synthase expression predicts the response to 5-fluorouracil-based adjuvant therapy in pancreatic cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  M. Talamini,et al.  Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. , 1997, Annals of surgery.

[7]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  J. Tepper,et al.  Tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  J. Radich,et al.  Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia. , 2004, Blood.

[10]  J. Mackey,et al.  Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy† , 2003, Oncogene.

[11]  E. Giovannetti,et al.  Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma , 2005, British Journal of Cancer.

[12]  Elisa Giovannetti,et al.  Cellular and Pharmacogenetics Foundation of Synergistic Interaction of Pemetrexed and Gemcitabine in Human Non–Small-Cell Lung Cancer Cells , 2005, Molecular Pharmacology.

[13]  M. Kornmann,et al.  Chemosensitivity testing and test-directed chemotherapy in human pancreatic cancer. , 2003, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[14]  J. Abbruzzese.  New applications of gemcitabine and future directions in the management of pancreatic cancer , 2002, Cancer.

[15]  F. D. De Braud,et al.  Pharmacogenetic determinants of anti-cancer drug activity and toxicity. , 2001, Trends in pharmacological sciences.

[16]  A. Mazo,et al.  Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2',2'-difluorodeoxycytidine- induced cytotoxicity. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  H. Ishitsuka,et al.  The antiproliferative activity of DMDC is modulated by inhibition of cytidine deaminase. , 1998, Cancer research.

[18]  E. Giovannetti,et al.  Synergistic Cytotoxicity and Pharmacogenetics of Gemcitabine and Pemetrexed Combination in Pancreatic Cancer Cell Lines , 2004, Clinical Cancer Research.

[19]  John R. Mackey,et al.  The Absence of Human Equilibrative Nucleoside Transporter 1 Is Associated with Reduced Survival in Patients With Gemcitabine-Treated Pancreas Adenocarcinoma , 2004, Clinical Cancer Research.

[20]  Dawei Xu,et al.  Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide , 2001, British journal of haematology.

[21]  J. Neoptolemos,et al.  Conclusions from the European Study Group for Pancreatic Cancer adjuvant trial of chemoradiotherapy and chemotherapy for pancreatic cancer. , 2004, Surgical oncology clinics of North America.

[22]  S. Ashley,et al.  RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine , 2004, Oncogene.

[23]  D. Hedley,et al.  Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity. , 2000, Cancer research.

[24]  C. R. Crawford,et al.  Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. , 1998, Cancer research.

[25]  E. Felip,et al.  Gene Expression as a Predictive Marker of Outcome in Stage IIB-IIIA-IIIB Non-Small Cell Lung Cancer After Induction Gemcitabine-Based Chemotherapy Followed By Resectional Surgery , 2004, Clinical Cancer Research.

[26]  R. Hruban,et al.  Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays , 2004, Oncogene.

[27]  Y. Yen,et al.  Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. , 1999, Cancer research.

[28]  G. Sakorafas,et al.  Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective. , 2000, Cancer treatment reviews.

[29]  G. Peters,et al.  Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. , 2002, Molecular cancer therapeutics.

[30]  C. Pilarsky,et al.  Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. , 2004, Neoplasia.