Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer.
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.


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.


CONCLUSIONS
Our results suggest that hENT1 plays an important role in 5-FU resistance and that hENT1 mRNA levels might be a useful marker to predict 5-FU sensitivity in pancreatic cancer.
Tsujie
Masanori
M
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University E2, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nakamori
Shoji
S
Nakahira
Shin
S
Takahashi
Yuji
Y
Hayashi
Nobuyasu
N
Okami
Jiro
J
Nagano
Hiroaki
H
Dono
Keizo
K
Umeshita
Koji
K
Sakon
Masato
M
Monden
Morito
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D033721:Equilibrative Nucleoside Transporter 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D012333:RNA, Messenger; C438649:SLC29A1 protein, human; D003841:Deoxycytidine; D005472:Fluorouracil; D000093542:Gemcitabine