title: Overexpression of thymidylate synthase mediates desensitization for 5-fluorouracil of tumor cells.
abstract: The prognosis of cancers of various organs overexpressing thymidylate synthase (TS) has been reported to be poor. It has been suggested that the poor prognosis is partly due to a low sensitivity of TS-overexpressing tumors to TS-targeting 5-fluorouracil (5-FU). To investigate the relationship between TS expression and sensitivity to 5-FU, we used the TS-overexpressing cervical cancer cell line SKG-II/TS and SKG-I/TS that had been established by TS gene transfer. The 50% growth inhibitory concentration (IC(50)) of 5-FU for SKG-II/TS was 24 +/- 6.0 microM, which was 6 times as high as that for the control (4.0 +/- 1.1 microM), showing significantly decreased sensitivity to 5-FU (p < 0.01). The IC(50) of 5-FU for SKG-I/TS was 90 +/- 15 microM, which was over 2 times as high as that for the control (40 +/- 0.6 microM), showing significantly decreased sensitivity to 5-FU (p < 0.05). Thus, TS-overexpressing tumors have decreased sensitivity to 5-FU, which may be one of the factors that determine the prognosis of these tumors.
authors.affiliation: Department of Obstetrics and Gynecology, Jichi Medical School, Yakushiji, Minamikawachi, Tochigi 329-0498, Japan. saga@jichi.ac.jp
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saga
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kohno
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takei
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D013940:Thymidylate Synthase / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D005472:Fluorouracil