Schedule-dependent antitumor effects of gemcitabine and S-1, a novel oral derivative of 5-fluorouracil, in human pancreatic cancer xenografts

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4154 Background: The systemic administration of gemcitabine (GEM) has been accepted as a standard treatment for patients with advanced pancreatic cancer. The major mediator of cellular uptake of GEM is the equilibrative nucleoside transporter 1 (ENT1) which expression is up-regulated by TS inhibitor such as 5-fluorouracil (5-FU). S-1 is a novel oral derivative of 5-FU prodrug tegafur combined with two modulators, 5-chloro-2, 4-dihydropridine and potassium oxonate, and recent clinical trials have reported the promising effect of S-1 in pancreatic cancer. The purpose of this study is to evaluate the relationship between different schedules and their effects of GEM/S-1 in combination therapy for pancreatic cancer in nude mouse xenograft model. Methods: Expression of ENT1 was determined by quantitative RT-PCR. GEM cellular uptake was determined using [3H]GEM. Seven pancreatic cancer cell lines (AsPC1, BxPC3, MiaPaCa-2, PSN1, Panc1, PCI6, and KMP4) were treated in vitro with 5-FU either before or following exposure to GEM. Growth inhibitory effects in vitro were determined by MTT assay. We compared 6 different treatment schedules (no treatment, single agent of GEM or S-1, combination treatment with gemcitabine either before, simultaneously or following administration of S-1) using MiaPaCa-2 xenograft model in BALB/c mice. The antitumor effects were evaluated with the tumor volume. Results: Significant increases in ENT1 expression and GEM cellular uptake were observed after 5-FU treatment in vitro and S-1 treatment in vivo. The in vitro growth inhibitory effect was significantly greater in the sequential treatment of 5-FU followed by GEM in all cell lines except for Panc1. Furthermore, the significant tumor growth inhibition in vivo was observed in the mice treated with S-1 followed by GEM compared with either untreated mice or the mice treated with gemcitabine followed by S-1. Conclusions: Based on the modulation of 5-FU on the uptake of GEM, 5-FU should be used before GEM treatment. The combination therapy with preadministarted S-1 and GEM in the patients with pancreatic cancer is promising and is worthwhile to be confirmed in clinical trials. No significant financial relationships to disclose.