Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer
Tsujie, M.; Nakamori, S.; Nakahira, S.; Takahashi, Y.; Hayashi, N.; Okami, J.; Nagano, H.; Dono, K.; Umeshita, K.; Sakon, M.; Monden, M.
Anticancer Research 27(4b): 2241-2249
2007
ISSN/ISBN: 0250-7005 PMID: 17695509 Document Number: 608333
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 I (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 [H-3] gemcitabine cellular uptake assay was performed to examine the inhibition of hENT1 by nitrobenzylmercaptoprine ribonucleoside (NBMPR). Results: The expression levels of hENT1 inRNA 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, [H-3] 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.