The optimal schedule for 5-fluorouracil radiosensitization in colon cancer cell lines.
To evaluate the optimal schedule of 5-fluorouracil (5-FU) radiosensitization in rectal cancer, we investigated the interaction between radiation and several doses of 5-FU on colon cancer cell lines based on pharmacokinetics of oral fluoropyrimidine. Cellular cytotoxicity in colon cancer cell lines, LoVo, WiDr and Caco-2 was determined, using a WST-8 colorimetric assay, after 24 h exposure to several concentrations of 5-FU and a radiation dose of 5 Gy. Cells were exposed to 5-FU 24 and 0 h before radiation. 5-FU doses were classified into three groups: uracil-tegafur (0.01-0.1 microM), S-1 (0.1-1.0 microM) and pharmacokinetic modulating chemotherapy (0.1-10 microM). In addition, the effect of 5-FU on the steady-state levels of a human excision repair cross-complementing 1 gene and cell cycle distribution were examined. Regardless of time of 5-FU exposure, all cell growth was significantly inhibited in a dose-dependent manner. In Caco-2 cells, the cytotoxicity of radiation followed by 5-FU was significantly greater than that of 5-FU followed by radiation, unlike in the other cell lines. The growth inhibitory effect of radiation followed by 5-FU increased in a dose-dependent manner to reach a plateau at S-1 doses in all cell lines. In cell cycle distribution, 5-FU exposure for 24 h increased the S phase fraction in a dose-dependent manner. RT-PCR showed that 5-FU post-treatment graduallly inhibited mRNA expression of ERCC1, which may affect recombination repair efficiency, accounting for the higher tumor sensitivity. Oral fluoropyrimidines, like S-1, that can maintain a constant level of 5-FU may be an acceptable alternative radiosensitizer to protracted 5-FU infusion, when the aim of neoadjuvant chemoradiotherapy for rectal cancer is locoregional control.
Ojima
Eiki
E
Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Inoue
Yasuhiro
Y
Watanabe
Hideki
H
Hiro
Junichiro
J
Toiyama
Yuji
Y
Miki
Chikao
C
Kusunoki
Masato
M
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D018938:Caco-2 Cells; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004720:Endonucleases / Q000096:biosynthesis / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D011838:Radiation-Sensitizing Agents; C071447:ERCC1 protein, human; D004720:Endonucleases; D005472:Fluorouracil