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Dual Antitumor Effects of 5-Fluorouracil on the Cell Cycle in Colorectal Carcinoma Cells: A Novel Target Mechanism Concept for Pharmacokinetic Modulating Chemotherapy

Second Department of Surgery [R. Y., M. K., H. Y., M. N., T. Y.], Department of Genetics [J. F., T. H-T.], and Institute for Advanced Medical Sciences [R. Y., M. K., T. Y., J. F., T. H-T.], Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan

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 "pharmacokinetic modulating chemotherapy" (PMC) regimen that we have advocated has proved to be highly effective in treating colorectal carcinoma. PMC consists of a continuous i.v. infusion of 5-FU over 24 h for 1 day a week at 600 mg/m²/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 months. 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 patients treated with the PMC regimen on the growth of three human colorectal adenocarcinoma cell lines, SW480 and COLO320DM (mutant p53) and HCT116 (wild-type p53). Exposure of these three cell lines to 5-FU resulted in growth inhibition in a dose-dependent manner. Exposure to 100 ng/ml of 5-FU in SW480 and COLO320DM caused G₁ arrest after 24 h and G₂ arrest after 72–144 h, and only a minority of the cell population showed apoptotic features, which indicated that most of the cells were killed through mitotic catastrophe, nonapoptotic cell death. On the contrary, exposure to 1000 ng/ml of 5-FU in SW480 and COLO320DM resulted in G₁-S-phase arrest and the induction of apoptosis throughout the experimental period. Nuclear cyclin B1 expression was markedly induced with exposure to 100 ng/ml of 5-FU in SW480 and COLO320DM; and expression of 14-3-3 protein, a cell cycle inhibitor in the G₂ phase, was induced in SW480. HCT116 responded to lower concentrations of 5-FU more rapidly: G₂ arrest was seen after 24–72 h of exposure to 10 ng/ml of 5-FU, and G₁ arrest was seen after 12–24 h of exposure to 100 ng/ml. These results show that 5-FU acts via two different pathways, depending on dose: (a) G₁-S-phase cell cycle arrest and apoptosis at 1000 ng/ml in SW480 and COLO320DM, and 100 ng/ml in HCT116; and (b) G₂-M-phase cell 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 PMC regimen is based on targeting at least two different phases of the cell cycle. In our clinical trial, we showed efficacy independent of p53 status, ascertained by cell kinetic analysis in vitro, which may lead to a novel concept of schedule-oriented biochemical modulation of this drug.

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