Nakata et al. Journal of Experimental & Clinical Cancer Research 2010, 29:15 http://www.jeccr.com/content/29/1/15 Page 6 of 7 tumor cells. S-1 is converted into 5-FU. An active meta- bolite of 5-FU is fluorodeoxyuridine monophosphate (FdUMP), which inhibits DNA synthesis by forming of ternary complex with 5,10-methylene tetrahydrofolate and thymidylate synthase. GEM inhibits ribonucleotid reductase, a key enzyme in the salvage pathway of pyri- midine biosynthesis. Consequently, GEM reduces the synthesis of deoxyuridine monophosphate, a major com- petitor of FdUMP, resulting enhancement of 5-FU cyto- toxicity [17]. Another potential mechanism is that 5-FU leads to an increase in cell surface human equilibrative nucleoside transporter 1 (hENT1) [18,19]. The most active GEM uptake is via hENT1. Thus, increased hENT1 expression by 5-FU may augment GEM cyto- toxicity by increasing GEM concentrations in tumor cells. In conclusion, the present study obtained by the lim- ited number of patients demonstrated the combination chemotherapy of S-1 with GEM did not affect the PK of each drug. As S-1 combined with GEM may be a pro- mising regimen, further investigations should be carried out to elucidate the synergistic mechanisms between the two drugs. List of abbreviations GEM: gemcitabine; 5-FU: 5-fluorouracil; PK: pharmaco- kinetics; Cmax: maximum concentration; AUCinf: area under the curve from the drug administration to the infinite time; T1/2: elimination half-life; Tmax: time required to reach Cmax; EGFR: epidermal growth factor receptor; DPD: dihydropyrimidine dehydrogenase; CDHP: 5-chloro-2,4-dihydrogenase; MST: median survi- val time; PS: performance status; i.v.: intravenously; HPLC: high-performance liquid chromatography; LC/ MS: high-performance liquid chromatographic-mass spectrometry; FdUMP: fluorodeoxyuridine monopho- sphate; hENT1: human equilibrative nucleoside trans- porter 1. Authors’ contributions BN have made substantially contribution to conception, design, data analysis, interpretation of data, and drafting the manuscript. RA, SN, TT, OS, TH, and YO have made substantial contributions to patients sample collection and acquisition of data. NY and KH have made contributions to revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Received: 4 January 2010 Accepted: 24 February 2010 Published: 24 February 2010 References 1. 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