Dual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: A novel target mechanism concept for pharmacokinetic modulating chemotherapy

Citation
R. Yoshikawa et al., Dual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: A novel target mechanism concept for pharmacokinetic modulating chemotherapy, CANCER RES, 61(3), 2001, pp. 1029-1037
Citations number
62
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
61
Issue
3
Year of publication
2001
Pages
1029 - 1037
Database
ISI
SICI code
0008-5472(20010201)61:3<1029:DAEO5O>2.0.ZU;2-W
Abstract
5-Fluorouracil (5-FU) is one of the most widely used anticancer agents for advanced colorectal carcinoma, but its response rate is only 15%, The "phar macokinetic modulating chemotherapy" (PMC) regimen that we have advocated h as proved to be highly effective in treating colorectal carcinoma. PMC cons ists of a continuous i.v. infusion of 5-FU over 24 h For 1 day a week at 60 0 mg/m(2)/day, and an oral dose of uracil-tegafur (UFT), a 5-FU derivative, at 400 mg/day for 5-7 days per week, repeated every week for more than 6 m onths. Assays of 5-FU in 23 patients receiving this treatment showed serum concentrations ranging from 88 to 1323 ng/ml, We then analyzed the effects of clinically relevant concentrations of 5-FU found in colorectal cancer pa tients treated with the PMC regimen on the growth of three human colorectal adenocarcinoma cell lines, SW480 and COLO320DM (mutant p53) and HCT116 (wi ld-type p53), Exposure of these three fell lines to 5-FU resulted in growth inhibition in a dose-dependent manner. Exposure to 100 ng/ml of 5-FU in SW 480 and COLO320DM caused G(1) arrest after 24 h and G(2) arrest after 72-14 4 h, and only a minority of the cell population showed apoptotic features, which indicated that most of the cells were killed through mitotic catastro phe, nonapoptotic cell death. On the contrary, exposure to 1000 ng/ml of 5- FU in SW480 and COLO320DM resulted in G(1)-S-phase arrest and the induction of apoptosis throughout the experimental period. Nuclear cyclin pi express ion was markedly induced with exposure to 100 ng/ml of 5-FU in SW480 and CO LO320DM; and expression of 14-3-3 sigma protein, a cell cycle inhibitor in the G(2) phase, was induced in SW480, HCT116 responded to lower concentrati ons of 5-FU more rapidly: G(2) arrest was seen after 24-72 h of exposure to 10 ng/ml of 5-FU, and G(1) arrest was seen after 12-24 h of exposure to 10 0 ng/ml. These results show that 5-FU acts via two different pathways, depe nding on dose: (a) G(1)-S-phase cell cycle arrest and apoptosis at 1000 ng/ ml in SW480 and COLO320DM, and 100 ng/ml in HCT116; and (b) G(2)-M-phase ce ll cycle arrest and mitotic catastrophe at 100 ng/ml in SW480 and COLO320DM , and 10 ng/ml in HCT116, These results suggest that the efficacy of our PM C regimen is based on targeting at least two different phases of the fell c ycle. In our clinical trial, we showed efficacy independent of p53 status, ascertained by cell kinetic analysis in vitro, which may lead to a novel co ncept of schedule-oriented biochemical modulation of this drug.