title: Dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells.
abstract: Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy.
authors.affiliation: Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Wakasa
authors.affiliation: Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Rumi
authors.initials: R
authors.lastname: Kawabata
authors.affiliation: Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Seiki
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Clinical Research Center, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Hattori
authors.affiliation: Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.affiliation: Department of Biostatistics, Yokohama City University, Yokohama, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.affiliation: Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.affiliation: Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oda
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008819:Mice, Nude; D013940:Thymidylate Synthase / Q000235:genetics*; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C000600377:TYMS protein, human; D013940:Thymidylate Synthase; D005472:Fluorouracil