Human Equilibrative Nucleoside Transporter 1, as a Predictor of 5-Fluorouracil Resistance in Human Pancreatic Cancer

Abstract

Background: The purpose of this study was to find a novel biomarker to predict 5-fluorouracil (5-FU) or gemcitabine (2′,2′-difluoro-deoxycytidine) sensitivity in pancreatic cancer. Materials and Methods: The relationship between 5-FU and gemcitabine sensitivity and the mRNA levels of human equilibrative nucleoside transporter 1 (hENT1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was investigated using seven types of human pancreatic carcinoma cell line (AsPC1, BxPC3, MiaPaCa-2, PSN1, Panc1, PCI6, and KMP-4). Quantitative mRNA expression was measured by LightCycler. A [³H] gemcitabine cellular uptake assay was performed to examine the inhibition of hENT1 by nitrobenzylmercaptoprine ribonucleoside (NBMPR). Results: The expression levels of hENT1 mRNA significantly correlated with the IC₅₀ value of 5-FU in all seven lines and also correlated with gemcitabine resistance in six lines (except AsPC1). No significant association was observed between TS or DPD mRNA levels and 5-FU sensitivity. In the PSN1 cells, [³H] gemcitabine uptake via hENT1 was significantly inhibited by NBMPR, and 5-FU sensitivity was significantly increased when the cells were pretreated with NBMPR. Conclusion: Our results suggest that hENT1 plays an important role in 5-FU resistance and that hENT1 mRNA levels might be a useful marker to predict5-FU sensitivity in pancreatic cancer.