The

regimen was stopped at the end of one course in one patient who could not continue oral intake of S-1 due to developing the stenosis at Treitz ligament by cancer invasion. The MST of total patients studied was 12.5 months, ranging from 3 to 22 months. The 1-year survival rates were 67%. One partial response was observed. SPan-1, one of reliable tumor marker for pancreatic cancer [9], titers in sera were decreased 50% or more in all of 5 patients who had abnormal level of SPan-1 prior to the treatment. MK-2206 in vivo Plasma PK There were no significant differences between plasma PK parameters of GEM after administration of GEM alone and GEM+S-1 (Table 1, Figure 2). There were no significant differences between the plasma PK parameters of 5-FU after administration of S-1 alone and GEM+S-1 (Table 2, Figure 3). Table 1 Comparison of pharmacokinetic parameters of gemcitabine (GEM) in plasma between administraion of GEM alone and GEM+S1   Cmax (ng/ml) AUCinf (hXng/ml) T1/2 (h) Day 1 15833 ± 2477 8467 ± 1092 0.12 ± 0.033 (GEM alone)       Day 15 14924 ± 5828 8384 ± 2915 0.153 ± 0.069 (GEM+S-1)       P-value 0.604 0.7406

0.1594 GEM was intravenously given at a dose of 800 mg/m2. S-1 was orally given at a dose of 30 mg/m2. Cmax, maximum plasma concentration; AUCinf, Small molecule library area under plasma concentration-time curve from time zero to infnite time; T1/2, elimination half-life. Titers are expressed as means ± SD (n = 6). P-values were examined by two-sided paired t-test after log-transformation. Table 2 Comparison of pharmacokinetic parameters of 5-fluorouracil in plasma between administration of S-1 alone Isotretinoin and gemcitabine (GEM)+S1   Cmax (ng/ml) AUCinf (hXng/ml) T1/2 (h) Tmax (h) Day 3 162 ± 46 853 ± 329 1.96 ± 0.73 3.16 ± 0.81 (S-1 alone)         Day 15 135 ± 56 682 ± 256 2.22 ± 0.84 3.07 ± 0.53 (GEM+S-1)         P-value 0.8644 0.2063 0.604 0.1683 GEM was intravenously given at a dose of 800 mg/m2 S-1 was orally given at a dose of 30 mg/m2. Cmax, maximum plasma concentration; AUCinf, area under plasma concentration-time curve from time zero to infnite time; T1/2, elimination half-life;

Tmax, the time required to reach Cmax. Titers were expressed as means ± SD (n = 6). P-values were examined by two-sided paired t-test after log-transformation. Figure 2 Plasma concentrations of gemcitabine (GEM) after administration of GEM 800 mg/m 2 alone (open circles) and GEM 800 mg/m 2 + S-1 30 mg/m 2 (closed circles). Figure 3 Plasma concentrations of 5-fluorouracil after administration of S-1 30 mg/m 2 alone (open circles) and GEM 800 mg/m 2 + S-1 30 mg/m 2 (closed circles). Discussion For the last decade, GEM monotherapy has been the standard chemotherapy regimen to treat advanced pancreatic cancer. The drug has an approximately 5% response rate and improves MST to less than 6 months [10]. Clinical trial data has demonstrated a response rate of 44-48% and an MST of 10.1-12.