title: Novel 5-fluorouracil-resistant human esophageal squamous cell carcinoma cells with dihydropyrimidine dehydrogenase overexpression.
abstract: 5-Fluorouracil (5-FU) is a key drug for the treatment of esophageal squamous cell carcinoma (ESCC); however, resistance to it remains a critical limitation to its clinical use. To clarify the mechanisms of 5-FU resistance of ESCC, we originally established 5-FU-resistant ESCC cells, TE-5R, by step-wise treatment with continuously increasing concentrations of 5-FU. The half maximal inhibitory concentration of 5-FU showed that TE-5R cells were 15.6-fold more resistant to 5-FU in comparison with parental TE-5 cells. TE-5R cells showed regional copy number amplification of chromosome 1p including the DPYD gene, as well as high mRNA and protein expressions of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU degradation. 5-FU treatment resulted in a significant decrease of the intracellular 5-FU concentration and increase of the concentration of α-fluoro-ureidopropionic acid (FUPA), a metabolite of 5-FU, in TE-5R compared with TE-5 cells in vitro. Conversely, gimeracil, a DPD inhibitor, markedly increased the intracellular 5-FU concentration, decreased the intracellular FUPA concentration, and attenuated 5-FU resistance of TE-5R cells. These results indicate that 5-FU resistance of TE-5R cells is due to the rapid degradation of 5-FU by DPD overexpression. The investigation of 5-FU-resistant ESCC with DPYD gene copy number amplification and consequent DPD overexpression may generate novel biological evidence to explore strategies against ESCC with 5-FU resistance.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kikuchi
authors.affiliation: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohashi
authors.affiliation: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: Department of Pharmacy, Kyoto University Hospital Kyoto 606-8507, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd. Tokushima 771-0194, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Matsuoka
authors.affiliation: Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd. Tokushima 771-0194, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobunai
authors.affiliation: Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd. Tokushima 771-0194, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Takechi
authors.affiliation: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Amanuma
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yoshioka
authors.affiliation: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan ; Department of Clinical Systems Onco-Informatics, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ida
authors.affiliation: Department of Clinical Systems Onco-Informatics, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Systems Onco-Informatics, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Gastroenterology Division, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Department of Pharmacy, Kyoto University Hospital Kyoto 606-8507, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto 606-8507, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Muto
keywords: 5-fluorouracil; Esophageal squamous cell carcinoma; chemotherapy; dihydropyrimidine dehydrogenase; drug resistance