The optimal schedule for 5-fluorouracil radiosensitization in colon cancer cell lines

Abstract

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 μM), S-1 (0.1-1.0 μM) and pharmacokinetic modulating chemotherapy (0.1-10 μM). In addition, the effect of 5-FU on the steadystate 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.

Combination chemotherapy of oxaliplatin and 5‐fluorouracil may be an effective regimen for mucinous adenocarcinoma of the ovary: A potential treatment strategy

“…Ojima et al . ( 34 ) reported that 5FU post‐treatment gradually inhibited mRNA expression of ERCC1 in colon cancer cell lines. Suppression of the protein expression of ERCC1 by 5FU may affect recombination DNA repair efficiency.…”

“…(20) We next attempted to elucidate the reason why this combination of L-OHP and 5FU contributes to the increasingly cytotoxic effect for MAC cells, and found that the protein expression levels of ERCC1 were down-regulated after treatment of 5FU both in vitro and in vivo. Ojima et al (34) reported that 5FU post-treatment gradually inhibited mRNA expression of ERCC1 in colon cancer cell lines. Suppression of the protein expression of ERCC1 by 5FU may affect recombination DNA repair efficiency.…”

Capecitabine Initially Concomitant to Radiotherapy Then Perioperatively Administered in Locally Advanced Rectal Cancer

“…In radiobiologic studies, an upregulation of TP expression was obtained by RT with an increased FU production in tumor tissues (8,9). Capecitabine has demonstrated similar activity with less toxicity than FU as folinic acid-modulated bolus or as protracted infusion, both in metastatic disease and in adjuvant settings; its role has also been investigated as preoperative indication (10)(11)(12).…”

Nanomedicine to overcome radioresistance in glioblastoma stem-like cells and surviving clones

“…In lung cancer, Chen et al showed that low-dose paclitaxel was sufficient for radiosensitization, and delayed irradiation was better than immediate irradiation following drug treatment [206]. In colon cancer cell lines, Ojima and coworkers showed that the cytotoxicity of radiation followed by 5-FU was significantly greater than for 5-FU followed by irradiation [207]. Thus, the optimal clinical schedule should be defined for all radiosensitizers based on preclinical and Phase I clinical trials.…”