Overexpression of thymidylate synthase mediates desensitization for 5-fluorouracil of tumor cells.
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.
Saga
Yasushi
Y
Department of Obstetrics and Gynecology, Jichi Medical School, Yakushiji, Minamikawachi, Tochigi 329-0498, Japan. saga@jichi.ac.jp
Suzuki
Mitsuaki
M
Mizukami
Hiroaki
H
Kohno
Takahiro
T
Takei
Yuji
Y
Fukushima
Masakazu
M
Ozawa
Keiya
K
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*
D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D005472:Fluorouracil