s-1-(combination) and gimeracil

The fluoropyrimidine anticancer agent 5-fluorouracil (5-FU) is active in a wide range of solid tumors, particularly gastric, colorectal, and head and neck cancers. Whilst infusional 5-FU is associated with higher response rates and a favorable safety profile as compared to the classical i.v. bolus administration, prolonged infusions can be inconvenient for the patients and catheter-related problems are common complications. An oral 5-FU formulation would allow for sustained 5-FU plasma concentrations, mimicking the pharmacokinetics (PK) of a continuous infusion with the addition of convenience of administration. The oral administration of 5-FU itself is not feasible due to the high activity of dihydropyrimidine dehydrogenase in the gut wall, which causes rapid metabolism of the drug, and results in decreased and erratic absorption of 5-FU and non-linear PK. To bypass this problem, oral fluoropyrimidine derivatives were developed either in the form of 5-FU prodrugs (i.e. tegafur, doxifluridine or capecitabine), or as enzyme inhibitors (i.e. eniluracil) administered with 5-FU, or as both prodrugs and enzyme inhibitors (i.e. S-1, UFT or BOF-A2). This review will focus on the oral fluoropyrimidine S-1, which consists of the 5-FU prodrug tegafur (ftorafur, FT) and two enzyme inhibitors, i.e. CDHP (5-chloro-2,4-dihydroxypyridine) and OXO (potassium oxonate), in a molar ratio of 1(FT):0.4 (CDHP):1(OXO). Phase II trials have demonstrated that S-1, as a single agent, is active for the treatment of gastric, colorectal, head and neck, breast, non-small cell lung, and pancreatic cancers. Phase III trials are currently underway in gastric cancer and these results are awaited to confirm the phase II findings. Furthermore, the combination of S-1 with cisplatin (CDDP), irinotecan or docetaxel for the treatment of gastric cancer and with CDDP for non-small cell and pancreatic cancer is feasible and active. The activity observed with S-1 in the phase II studies is at least equivalent, if not better, than continuous i.v. and bolus 5-FU and the other oral fluoropyrimidines. Thus, we may finally be seeing the realization of oral treatments for the management of various solid tumors and could be on the brink of a new approach to treatment strategies.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dosage Forms; Drug Administration Schedule; Drug Combinations; Drug Delivery Systems; Drug Evaluation, Preclinical; Enzyme Inhibitors; Gastrointestinal Neoplasms; Humans; Oxonic Acid; Prodrugs; Pyridines; Pyrimidines; Tegafur

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Gastrectomy; Humans; Male; Middle Aged; Models, Biological; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

We carried out a phase I/II trial of chemoradiotherapy concurrent with S-1 and cisplatin to determine the maximum tolerated dose and recommended dose and to evaluate the efficacy and safety of this treatment in patients with esophageal carcinoma. Thoracic esophageal cancer patients with clinical stage II/III disease, excluding T4, were eligible. Chemotherapy consisted of S-1 at a dose of 60-80 mg/m(2) /day on days 1-14, and cisplatin at 75 mg/m(2) on day 1, repeated twice every 4 weeks. Single daily radiation of 50.4 Gy was given in 28 fractions concurrently starting on day 1. Patients achieving an objective response after chemoradiotherapy underwent two additional cycles of chemotherapy. Patient accrual was terminated early due to slow enrolment after 44 patients were accrued. In the phase I part, two of six patients experienced dose-limiting toxicities at each level of S-1 (S-1 60 or 80 mg/m(2) /day). Considering treatment compliance, the recommended dose was determined to be S-1 60 mg/m(2) /day. The complete response rate, the primary endpoint of phase II, was 59.5% (22/37; 90% confidence interval, 44.6-73.1%; weighted threshold, 57.2%; P = 0.46 by the exact binomial test) on central review. In the phase II part, 3-year progression-free survival was 48.4%, with a 3-year overall survival of 61.9%. Grade 3 or 4 toxicity in phase II included leukopenia (57.9%), neutropenia (50%), hyponatremia (28.9%), anorexia (21.1%), anemia (18.4%), thrombocytopenia (18.4%), and febrile neutropenia (2.6%). No treatment-related deaths were observed. Although this combination showed acceptable toxicity and favorable 3-year survival, the study did not meet its primary endpoint. This trial was registered at the UMIN Clinical Trials Registry as UMIN000000710.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Disease-Free Survival; Drug Combinations; Esophageal Neoplasms; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Oxonic Acid; Prospective Studies; Pyridines; Radiotherapy Dosage; Tegafur; Treatment Outcome; Young Adult

S-1, an oral fluoropyrimidine, is usually given for 4 weeks (80 mg/m2/day) followed by a 2-week rest. However, compliance with this regimen is unsatisfactory because of adverse events such as leukopenia, anorexia, and nausea. To reduce adverse effects and improve compliance, we studied a "5-day on/2-day off" low-dose regimen of S-1 and evaluated pharmacokinetics in patients with non-small-cell lung cancer (NSCLC).. Twelve patients with NSCLC were divided into 2 groups and received S-1 in a dose of 25 mg twice daily (level 1, n = 6) or 40 mg twice daily (level 2, n = 6) for 5 consecutive days followed by a 2-day rest (5 days on/2 days off) every week. Plasma 5-fluorouracil (5-FU) concentrations were measured.. The maximum concentration in plasma and the area under the plasma concentration-time curve from 0 to 9 h were respectively 55.3 ± 21.1 ng/ml and 290.2 ± 95.7 ng·hr/ml for level 1, as compared with 104.2 ± 33.5 ng/ml and 541.9 ± 232.3 ng·hr/ml for level 2. These values were similar to those previously reported for a continuous intravenous infusion of 5-FU. Adverse events were grade 1 fatigue (n = 1 in each group) and anorexia (n = 1 in each group).. A "5-day on/2-day off" low-dose (40 mg twice daily) regimen of S-1 is feasible for the treatment of NSCLC, with acceptable plasma 5-FU concentrations and minimal adverse effects. A phase II or III trial of this regimen in an adjuvant setting is warranted in patients with NSCLC.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Drug Combinations; Female; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Patient Compliance; Pyridines; Tegafur; Treatment Outcome

This pharmacokinetic study of S-1 was conducted in patients in whom glomerular filtration rate (GFR) was directly measured to explore the possibility of adjusting the S-1 dose on the basis of GFR in patients with normal or nearly normal renal function.. S-1 was given to 12 patients twice daily for 28 consecutive days followed by 14 days of rest, repeated every 6 weeks. GFR was measured on the basis of inulin clearance (CLin) before the first day of treatment.. The area under the time-concentration curve (AUC) of 5-fluorouracil (5-FU) correlated with that of 5-chloro-2,4-dihydroxypyridine (CDHP, r = 0.750, p = 0.005). The AUC of CDHP correlated with the measured 24-hour creatinine clearance (CLcr) per subject (r = -0.620, p = 0.032), but not with the CLin (r = -0.356, p = 0.257). The AUC of 5-FU did not correlate with either the 24-hour CLcr per subject (r = -0.401, p = 0.187) or with the CLin (r = -0.300, p = 0.351).. Dosage adjustment based on the GFR does not reduce individual variations in 5-FU concentrations among patients with normal or nearly normal renal function who receive S-1.

Topics: Aged; Antimetabolites, Antineoplastic; Area Under Curve; Creatinine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Glomerular Filtration Rate; Humans; Inulin; Kidney Function Tests; Male; Middle Aged; Oxonic Acid; Pyridines; Reference Values; Tegafur

The purpose of this study was to investigate the effect of gimeracil (CDHP), a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor, on the pharmacokinetics of 5-fluorouracil (5-FU) and other related metabolites by comparing the pharmacokinetic (PK) profile of S-1 (tegafur [FT] + CDHP + oteracil potassium [Oxo]) to that of FT alone.. Patients with advanced solid tumors received single oral doses of S-1 (50 mg) and FT (800 mg) on days 1 and 8 in a randomized crossover fashion. Plasma samples were collected on days 1, 2, 3, 8, 9 and 10. Single-dose PK parameters were determined for FT, 5-FU and α-fluoro-β-alanine (FBAL). Following the single-dose crossover period, patients entered an extension phase and received treatment with S-1 b.i.d. for 14 days followed by a 7-day rest, repeated every 3 weeks.. A total of 12 patients were enrolled; median age was 59 years and mean body surface area was 1.94 m(2). Following S-1 administration, 5-FU exposure was significantly greater (approximately 3-fold) compared to FT alone (p ≤ 0.0007 for AUC0-inf, AUC0-last, and C(max) of 5-FU) despite the 16-fold higher dose of FT administered alone compared to S-1, while plasma concentrations of FT and FBAL were significantly lower with S-1 (p < 0.0001 for all comparisons). Following both single- and multiple-dose administration of S-1, the average maximum DPD inhibition was observed at 4 h post-dose. The extent of inhibition was similar following single and multiple dosing. Following single- and multiple-dose administration of S-1, plasma concentrations of uracil returned to baseline levels within approximately 48 h of dosing, indicating reversibility of DPD inhibition by CDHP.. Despite the differences in the FT dose administered, exposure to 5-FU was significantly greater following S-1 administration compared to FT administration. Conversely, exposure to FT and FBAL were significantly less following S-1 administration compared to FT administration. Thus, the DPD inhibitory action of CDHP contributes to a decrease in 5-FU catabolism and to significantly higher blood levels of 5-FU compared to FT alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cross-Over Studies; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Drug Interactions; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Tegafur

Optimal chemotherapy for advanced biliary tract cancer (BTC) is yet to be defined. We carried out this study to evaluate the efficacy and toxicity of combination chemotherapy with S-1 and cisplatin in metastatic or relapsed BTC.. Patients with pathologically proven BTC were eligible. The chemotherapy regimen consisted of S-1 (40 mg/m(2) p.o. b.i.d. from D1-14) and cisplatin (60 mg/m(2) on D1), repeated every 3 weeks.. Fifty-one BTC patients (metastatic:relapsed = 37:14, Gall-bladder:intrahepatic bile ducts:extrahepatic bile ducts = 16:25:10) were enrolled from January 2005 to December 2006. Median age was 57 years (range, 31-71) and most patients had a good performance status. The overall response rate was 30% [95% confidence interval (CI), 17.3-42.7] and complete response was observed in two patients (4%), partial response in 13 (26%), stable disease in 21 (42%), and progressive disease in 9 (18%). With a median follow-up of 12.4 months, the median time to progression was 4.8 months (95% CI, 3.3-6.3) and median overall survival was 8.7 months (95% CI, 6.0-11.4). Major toxic effects were grade 3/4 neutropenia (8.9% of all cycles) and febrile neutropenia was observed in six cycles (2.7% of all cycles).. Combination chemotherapy with S-1 and cisplatin was a moderately effective outpatient-based regimen in BTC patients. Toxic effects were moderate but manageable.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Cisplatin; Disease Progression; Disease-Free Survival; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neutropenia; Oxonic Acid; Pyridines; Salvage Therapy; Survival Analysis; Tegafur; Thrombocytopenia

S-1 is an oral anticancer agent composed of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. CDHP is added to prevent degradation of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase. CYP2A6 is involved in the biotransformation of FT to 5-FU. Thus, we prospectively analyzed the effects of the CYP2A6 genotype, plasma level of CDHP, and patient characteristics on the pharmacokinetic (PK) variability of FT and 5-FU. Fifty-four Japanese patients with metastatic or recurrent cancers who received S-1 were enrolled. The CYP2A6 polymorphisms (*4A, *7, and *9) with deficient or reduced activity were analyzed. All subjects were classified into three groups according to their CYP2A6 genotype: wild type (*1/*1), one-variant allele (*1/any), or two-variant alleles (combination other than *1). The PK of FT, 5-FU, and CDHP were measured on day 1 of treatment. Multivariate regression analysis revealed that oral clearance of FT was associated with the CYP2A6 genotype (analysis of variance [ANOVA], P = 0.000838). The oral clearance of FT seen in patients with the two-variant alleles was significantly lower than those in wild type and the one-variant allele (95% confidence intervals 0.75-2.41 and 0.41-1.82, respectively; Tukey-Kramer test). The area under the time-concentration curve (AUC) of 5-FU was significantly correlated with the AUC of CDHP (ANOVA, P = 0.00126). The AUC of 5-FU and CDHP were inversely correlated with creatinine clearance (ANOVA, P = 0.0164 and P = 0.000762, respectively). Although the CYP2A6 variants are the cause of the PK variability of FT, the AUC of CDHP affected by renal function is the key determinant of the variability in the PK of 5-FU.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Aryl Hydrocarbon Hydroxylases; Asian People; Cytochrome P-450 CYP2A6; Drug Combinations; Female; Fluorouracil; Genotype; Humans; Male; Middle Aged; Mixed Function Oxygenases; Neoplasms; Oxonic Acid; Polymorphism, Genetic; Pyridines; Tegafur

TS-1 is a combination preparation of tegafur, a prodrug of 5-fluorouracil (5-FU), with gimeracil, a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), which mediates the inactivation of 5-FU. UFT is a combination preparation of tegafur with uracil, which also inhibits DPD, though less potently; UFT has a higher content of tegafur than that in TS-1. We aimed to develop a pharmacokinetic model to describe the kinetics of tegafur and 5-FU after the administration of TS-1 and UFT.. We developed a model incorporating the inhibition of DPD by gimeracil and uracil, and fitted the model to the observed kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. Then, we simulated the plasma 5-FU profiles in patients with renal dysfunction and those after replacement of TS-1 with UFT and compared them with the observed profiles.. The developed model could appropriately describe the plasma concentration profiles of 5-FU and tegafur after the administration of TS-1 in patients with normal and impaired renal function.. The developed model may be useful to optimize the dosage regimen of TS-1 under various clinical conditions.

Topics: Administration, Oral; Algorithms; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Computer Simulation; Drug Combinations; Fluorouracil; Humans; Kidney; Kinetics; Models, Biological; Oxonic Acid; Pyridines; Renal Insufficiency; Tegafur; Time Factors; Uracil

The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated.. A dose of 40 mg/m(2) of S-1 was administered orally twice daily for 7 days (80 mg/m(2)/day) preoperatively in ten patients with resectable gastric cancer, and the same dose of S-1 was administered for 28 consecutive days after gastrectomy. Plasma concentrations of tegafur, gimeracil, and oteracil potassium, all the components of S-1, and 5-FU were measured on pre- and postoperative days. Concentrations of 5-FU in tumor and normal tissues were also determined.. At day 4 from the initial preoperative administration of S-1, the AUC of 5-FU was 1,055 +/- 304 ng h/ml. At day 18, day 28, and day 42 after gastrectomy, it was 1,012 +/- 331, 1,070 +/- 403, and 946 +/- 226 ng h/ml, respectively. No significant differences for plasma 5-FU were observed between pre- and postoperative days. In the resected tumor tissues, concentrations of 5-FU were 242 +/- 83 ng/g around 4.5 h and 91.7 +/- 37.0 ng/g around 20 h after the final administration, respectively.. Gastrectomy does not affect on pharmacokinetics of 5-FU derived from S-1 regardless of partial or total gastrectomy, indicating that S-1 can be a useful drug in postoperative adjuvant chemotherapy for gastric cancer.

Topics: Administration, Oral; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Drug Combinations; Female; Fluorouracil; Gastrectomy; Humans; Male; Middle Aged; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

5-Fluorouracil (5-FU) or a 5-FU derivative 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) has been widely prescribed for patients with gastrointestinal cancer. However, the phosphorylation of 5-FU in the digestive tract causes gastrointestinal toxicities. 5-FU is also rapidly degraded to alpha-fluoro-beta-alanine after contact with dihydropyrimidine dehydrogenase (DPDase) which is mainly present in the liver. Therefore, to overcome these metabolic events, S-1, an antitumor agent was developed, based on the biochemical modulation of FT by 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo), in a molar ratio of 1:0.4:1. The antineoplastic effect of S-1, was examined in Japanese patients with advanced gastric (G) or colorectal (C) cancer in a multicenter early phase II study involving 24 centers throughout Japan. The patients were prescribed a minimum of 2 courses of S-1 orally, with each course consisting of 75 or 50 mg (in terms of FT) twice a day for 28 days followed by withdrawal for 2 weeks. Thirty-one patients with G and 31 C were entered into this study. The clinical response and extent of toxicity were evaluated in G 28 and C 30 cases, respectively. Nine (32.1%) G patients and 14 (46.7%) C patients had been treated previously with other anticancer drugs. In G patients, there was a 53.6% (15/28) and in C patients a 16.7% (5/30) response rate (90% confidence interval G 38.4-68.1% and C 8.4-30.5%) with 15 (53.6%) (G) and 5 (16.7%) (C) partial responses (PR), and these responses persisted for 79 days (G) and 120 days (C) (median value). In particular, the response rate for the primary lesion was 27.8% (5/18) (G) and 33.3% (1/3) (C). No change (NC) in the disease was observed in 4 (14.3%) (G) and 13 (43.3%) (C) patients, and in 6 (21. 4%) (G) and 7 (23.3%) (C) the disease progressed (PD). At the time of analysis, the median survival was 298 days (G) and 358 days (C). Major adverse effects consisted of gastrointestinal symptoms and myelosuppression while toxicities of grade 3 or more occurred in 35. 7% (10/28) (G) and 33.3% (10/30) (C). Based on these data, S-1 is considered to have positive effects in patients with advanced gastrointestinal cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Drug Combinations; Fluorouracil; Gastrointestinal Neoplasms; Humans; Male; Middle Aged; Oxonic Acid; Pyridines; Survival Analysis; Tegafur; Treatment Outcome

Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown. Here, we investigated the antitumor mechanism of the combination of C-REV and S-1 in triple-negative breast cancer (TNBC) in the context of tumor immunity. The combined effect of C-REV and S-1 was evaluated in a bilateral tumor model of murine TNBC 4T1 in vivo. S-1 enhanced the TNBC growth inhibitory effects of C-REV, and decreased the number of tumor-infiltrating, myeloid-derived suppressor cells (MDSCs), which suppress both innate and adaptive immune responses. Moreover, C-REV alone and in combination with S-1 significantly increased the number of CD8

Topics: Animals; Antimetabolites, Antineoplastic; CD8-Positive T-Lymphocytes; Drug Combinations; Fluorouracil; Humans; Mice; Neoplasm Recurrence, Local; Oncolytic Viruses; Oxonic Acid; Pyridines; Tegafur; Triple Negative Breast Neoplasms

For the past 20 years, S-1 has been used in the treatment of many types of cancer. However, the clinical importance of myocardial dysfunction attributed to S-1 remains to be unclear. Thus, in this study, we report on a patient with myocardial dysfunction associated with S-1.S-1 postoperative chemotherapy for gastric cancer was included as a treatment for a 65-year-old man. On day 8, S-1 treatment was discontinued after the patient developed an oral ulcer. He was then admitted to the hospital because of diarrhea caused by S-1. At approximately the same time, he developed dyspnea, and his chest X-rays revealed perihilar vascular engorgement and cardiac enlargement. Although his brain natriuretic peptide was 595.8 pg/mL, troponin I and creatine phosphokinase were unremarkable. Electrocardiograms showed no change in atrial fibrillations or new ST-T wave change. As per his transthoracic echocardiogram, noted were expansion of the left ventricle, global hypokinesis, and reduced left ventricular ejection fraction (approximately 40%). The patient was then diagnosed with S-1-related myocardial dysfunction. Furosemide, human atrial natriuretic peptide, dobutamine, enalapril, spironolactone, and bisoprolol were administered. Thirteen days after being diagnosed with heart failure, his symptoms disappeared, his echocardiogram showed that the left ventricular ejection fraction had increased to 65%, and the cardiothoracic ratio improved to 47% according to his chest X-rays.S-1-related myocardial dysfunction may be reversible, as it can improve after approximately 2 weeks.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Drug Combinations; Humans; Male; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

Adjuvant chemotherapy has changed the paradigm in resectable gastric cancer. S-1 is an oral chemotherapeutic with promising efficacy in Asia. However, comparisons with close observation or platinum-based doublets post D2 gastrectomy have been less reported, notably on real-world experiences.. We retrospectively evaluated patients with D2-dissected stage IB-III gastric cancer who received S-1 (S-1, n = 67), platinum-based doublets (P, n = 145) and surgery with close observation (OBS, n = 221) from Jan 2008 to Oct 2018. A propensity score matching was used to compare for recurrence-free (RFS) and overall survivals (OS) in patients who had a locally-advanced disease (T3-4 or lymph node-positive). Adverse reactions, dosage, and associated factors for S-1 are also discussed.. In a median follow-up time of 51.9 months, adjuvant S-1 monotherapy was associated with an intermediate survival as compared with P and OBS (median RFS/OS: S-1 vs. P, 20.9/35.8 vs. 31.2/50.5 months, HR = 1.76/2.14, p = 0.021/0.008; S-1 vs. OBS, 24.4/40.2 vs. 20.7/27.0 months, HR = 0.62/0.55, p = 0.041/0.024). The survival differences were more prominent in patients with N2-3 diseases. S-1 was well-tolerated with a relative dose intensity of 73.6%, a median duration of 8.3 months and associated with less adverse reactions as compared with P. S-1 monotherapy was selected by physicians based on age, lymph node stage, serum carcinoembryonic antigen and disease stage.. Adjuvant S-1 correlated with intermediate survival outcomes between OBS and P but conferred fewer adverse reactions as compared with P. Patients with a moderate risk of recurrence had comparable survivals when treated with S-1 while platinum-based doublets were favored in advanced cases. The study provides additional information about adjuvant S-1 in patients with selected risk of recurrence.

Topics: Aged; Chemotherapy, Adjuvant; Drug Combinations; Humans; Middle Aged; Oxonic Acid; Propensity Score; Pyridines; Retrospective Studies; Stomach Neoplasms; Tegafur

Prognosis of patients with metastatic gastric cancer is abysmal, usually just a few months. S-1 is a peroral fluoropyrimidine antitumor drug. It is a fixed combination of three effective drugs - tegafur, gimeracil and oteracil potassium.. This is a case report of a 71-year-old man treated for local advanced and metastatic gastric carcinoma treated with combination of S-1 and cisplatin as a first line of therapy. Treatment response reached partial remission and lasted for six months. Treatment was very well tolerated, with no grade 3 and 4 toxicity. After progression, the patient was treated with further lines of therapy.. In the Czech Republic, experience with S-1 drug is very limited. Our case report showed a good treatment response and minimal toxicity of this treatment, in concordance with results of the study FLAGS.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Czech Republic; Drug Combinations; Humans; Male; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Treatment Outcome

The study is to investigate the pharmacokinetics of S-1 capsule (tegafur, gimeracil and potassium oxonate capsule) in patients with advanced gastric cancer after single and multiple oral administration. Twelve patients with advanced gastric cancer were recruited to the study. The dose of S-1 for each patient was determined according to his/her body surface area (BSA). The dose for single administration was 60 mg every subject. The dose for multiple administration for one subject was as follows: 100 mg x d(-1) or 120 mg x d(-1), 28-days consecutive oral administration. The pharmacokinetic parameters of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil after single oral administration were as follows: (2,207 +/- 545), (220.0 +/- 68.2), (374.9 +/- 103.0), (110.5 +/- 100.8) and (831.1 +/- 199.9) ng x mL(-1) for Cmax; (11.8 +/- 3.8), (4.4 +/- 3.3), (7.8 +/- 5.1), (3.1 +/- 0.9) and (8.8 +/- 4.1) h for t1/2, respectively. After six days oral administration, the average steady state plasma concentrations (Cav) of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil were (2,425 +/- 1,172), (73.88 +/- 18.88), (162.6 +/- 70.8), (36.89 +/- 29.35) and (435.3 +/- 141.0) ng x mL(-1), respectively, and the degree of fluctuation (DF) were (1.0 +/- 0.2), (2.5 +/- 0.4), (3.1 +/- 0.8), (2.4 +/- 0.8) and (1.5 +/- 0.3), respectively. The cumulative urine excretion percentage of tegafur, 5-fluorouracil, gimeracil and potassium oxonate in urine within 48 h were (4.2 +/- 2.8) %, (4.7 +/- 1.6) %, (18.5 +/- 6.0) % and (1.7 +/- 1.2) %, repectively, after single oral administration of S-1. The results exhibited that tegafur had some drug accumulation observed, and gimeracil, potassium oxonate, 5-fluorouracil and uracil had no drug accumulation observed.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Capsules; Drug Combinations; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Uracil

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm. S-1 has been developed as a novel oral antineoplastic agent based on the modulation of 5-fluorouracil (5-FU) bioactivity. This study was conducted to investigate the preclinical therapeutic effect of S-1 on MPM.. We used three human MPM cell lines, Y-MESO-14, NCI-H290 and MSTO-211H. In vitro proliferation of human MPM cells was determined by MTT assay. Human MPM cells were orthotopically implanted into thoracic cavity of SCID mice. Tumor-bearing mice were treated with S-1 or vehicle.. The combination of 5-FU and 5-chloro-2,4-dihydroxypyridine (CDHP) was more effective than 5-FU alone in inhibiting MPM cell proliferation in vitro. This combination was most effective in Y-MESO-14 cells, which co-expressed high protein level of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP). In vivo data showed that treatment with S-1 significantly reduced thoracic tumors and pleural effusion produced by Y-MESO-14 cells. Moreover, treatment with S-1 prolonged the survival of Y-MESO-14 cell-bearing SCID mice.. We demonstrated that S-1 was effective for inhibiting the proliferation of MPM cells, particularly with both DPD and TP expressions, suggesting that S-1 might be therapeutically effective for control of MPM.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Humans; Male; Mesothelioma; Mice; Mice, SCID; Neoplasm Proteins; Oxonic Acid; Pentosyltransferases; Pleural Neoplasms; Pyridines; Random Allocation; Survival Analysis; Tegafur; Thymidine Phosphorylase; Tumor Burden; Xenograft Model Antitumor Assays

In this study, we evaluated the feasibility, efficacy and toxicity of concurrent chemoradiotherapy with S-1 (tegafur-gimeracil-oteracil potassium) for T2N0 glottic carcinoma. A total of 23 patients with T2N0 glottic carcinoma received chemoradiotherapy with S-1. Radiotherapy consisted of five daily fractions of 2 Gy per week, to a total median dose of 70 Gy. S-1 was administered 65 mg/m(2) per day for 4 weeks, beginning on the day therapy was started, followed by 2 weeks off the drug and twice a day until the end of radiotherapy. Initial local control rate of the primary tumor was achieved in all patients. The median follow-up period for all patients was 38 months. The 3-year local control rate was 95.4%. Regarding adverse reactions, grade 3 mucositis upon clinical examination, mucositis upon functional/symptomatic examination, dysphagia, hepatic toxicity and anemia were observed in 13, 2, 2, 1 and 1 patients, respectively. This chemoradiotherapy did not result in grade 4 acute toxicity or severe late toxicity. Chemoradiotherapy with S-1 was feasible, well tolerated and effective. This therapy is suggested as a possible regimen for improving local control of T2N0 glottic carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Combinations; Glottis; Humans; Kaplan-Meier Estimate; Laryngeal Neoplasms; Male; Middle Aged; Oxonic Acid; Pyridines; Radiation-Sensitizing Agents; Tegafur

Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin, UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a dose of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dose-dependent manner. Furthermore, we observed decreased expression of γ-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Combined Modality Therapy; Drug Combinations; Fluorouracil; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Oxonic Acid; Pyridines; Radiation-Sensitizing Agents; Tegafur; Whole-Body Irradiation; Xenograft Model Antitumor Assays

Chemosensitivity tests have long been discussed but remain a topic of research. In this study, we investigated the correlation between the results of a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine and the clinical outcomes of gastric cancer patients treated with S-1, an oral fluoropyrimidine, as adjuvant chemotherapy.. For gastric cancer patients, we performed surgical treatment and a lymph node dissection of D2 or more. Afterwards, a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine was performed, using the collagen gel droplet embedded culture drug-sensitivity test (CD-DST), in surgical specimens. All the patients received postoperative adjuvant chemotherapy with S-1 for 1 year, and the overall survival (OS), relapse-free survival (RFS), and adverse events were investigated.. The chemosensitivity test was performed for 27 patients. The growth inhibition rate (IR) was 50% or more (high-sensitivity group) in 59.3% (16 cases) and it was under 50% (low-sensitivity group) in 40.7% (11 cases). The 3-year OS rate was 100% in the high-sensitivity group and 62.34% in the low-sensitivity group. The 3-year RFS rate was 83.33% in the high-sensitivity group and 24.24% in the low-sensitivity group. Thus, the 3-year OS rate and the 3-year RFS rate were higher in the high-sensitivity group than in the low-sensitivity group. No adverse events of grade 3 or greater severity were observed.. The results of the chemosensitivity test were correlated with the patient outcome. Therefore, such results might be useful for individualizing cancer chemotherapy and for determining future indications for postoperative adjuvant chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Oxonic Acid; Postoperative Care; Predictive Value of Tests; Pyridines; Stomach Neoplasms; Survival Analysis; Tegafur; Treatment Outcome

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Anti-Ulcer Agents; Antimetabolites, Antineoplastic; Area Under Curve; beta-Alanine; Biological Availability; Clinical Trials as Topic; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Fasting; Fluorouracil; Food; Gastric Acidity Determination; Half-Life; Humans; Hydrogen-Ion Concentration; Oxonic Acid; Pantoprazole; Pyridines; Tegafur; Triazines; Uracil

We reported the first case of phenytoin intoxication due to the concomitant use of phenytoin and TS-1, together with a review of the literature regarding the occurrence of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs such as fluorouracil (5-FU) and tegafur (FT).. We showed the clinical course of our patient. Reports of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs in the English and Japanese language literature up to 2007 were identified by searching Medline and ICHUSHI Web (Japana Centra Revuo Medicina).. A patient taking phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium, experienced lightheadedness and repeated falls associated with an increase in serum phenytoin concentration (32.8 mug/ml) at 1 month after the start of TS-1 treatment. The time lag between initiation of combined treatment and onset of adverse symptoms suggests the presence of an indirect mechanism, rather than direct inhibition of drug-metabolizing enzymes by drugs in TS-1 or their active metabolites.. Plasma phenytoin concentration should be closely monitored in patients receiving TS-1 and phenytoin concomitantly.

Topics: Aged; Antimetabolites, Antineoplastic; Drug Combinations; Drug Interactions; Humans; Male; Oxonic Acid; Phenytoin; Pyridines; Tegafur

The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated in a total of 12 cases - nine in which partial gastrectomy was performed and three in which total gastrectomy was performed. A single oral dose of S-1, 50 mg as tegafur, was administered, serial peripheral blood samples were collected, and the concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured. The pre-operative S-1 dose was administered about 7 days before surgery and the post-operative dose was administered around post-operative hospital day 14. In the partial gastrectomy cases the maximum post-operative blood concentration (Cmax) of 5-FU and CDHP tended to be lower than before surgery, and the difference in 5-FU concentrations was significant. The area under the blood concentration-time curve (AUC0-8 h) for CDHP was significantly smaller post- than pre-operatively, but no significant difference was observed with regard to 5-FU. In the total gastrectomy cases the post-operative tmax of both 5-FU and CDHP was shorter than the pre-operative tmax, and no significant differences were observed between the pre- and post-operative AUC0-8 h values. Thus, the results of the present study showed that around post-operative hospital day 14, when total oral feeding had become possible after surgery for gastric cancer, the AUC0-8 h values of 5-FU and CDHP after S-1 administration were almost the same as before surgery and that gastrectomy had hardly any effect on the pharmacokinetics of S-1.

Topics: Administration, Oral; Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Fluorouracil; Gastrectomy; Humans; Male; Middle Aged; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Time Factors

The response of gastric cancer with peritoneal dissemination to systemic chemotherapy may be negatively affected by poor drug delivery due to the blood-peritoneal barrier. However, S-1 has been reported to be effective. We examined the pharmacokinetics of S-1 in 14 patients who had gastric cancer with peritoneal dissemination. S-1 was given from the morning of the day before surgery to the morning of surgery. Concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured in the serum, ascites, disseminated peritoneal nodes, and normal peritoneum. There was a strong correlation between 5-FU and CDHP concentrations in peritoneal tissues. The concentrations of 5-FU and CDHP in the serum were similar to those in ascites. The concentration of 5-FU was significantly higher in disseminated nodes than in the normal peritoneum. After administration of S-1 to gastric cancer patients with peritoneal dissemination, 5-FU and CDHP in the serum linearly pass through the peritoneum and enter the ascites. High concentrations of 5-FU selectively penetrate disseminated peritoneal cells.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Biological Availability; Drug Combinations; Female; Fluorouracil; Humans; Lymph Nodes; Male; Middle Aged; Oxonic Acid; Peritoneal Neoplasms; Peritoneum; Pyridines; Stomach Neoplasms; Tegafur

The optimum dose of TS-1 for the treatment of peritoneally disseminated gastric cancer in a patient with chronic renal failure undergoing chronic dialysis was estimated by monitoring the blood concentrations of 5-FU and gimeracil (CDHP) [therapeutic drug monitoring (TDM)] during administration of TS-1. Immediately after dialysis, 50 mg or 40 mg of TS-1, corresponding to 50% and 40% of the standard dose (100mg for this patient), respectively, was administered orally once a day every other day, and TDM was conducted. Compared with the pharmacokinetic parameters of 5-FU at the time of the initial administration of 50 mg or 40 mg of TS-1 and that of cancer patients with normal renal function, the AUC shown in the administration of 40 mg was equivalent to that observed with a single safe dose of 100 mg in patients with normal renal function. Based on this observation, the daily TS-1 dose was set at 40 mg in this patient, and TS-1 treatment was started after confirming the absence of the accumulation of 5-FU or CDHP during repeated administrations. In this treatment protocol, TS-1 was administered 11 times at a daily dose of 40 mg every other day immediately after dialysis, followed by a rest. This .administration schedule was defined as one course. Under these conditions, the patient was treated on an outpatient basis, and the treatment could be safely continued without the development of any severe adverse events, such as myelosuppression.

Topics: Adenocarcinoma; Adult; Antimetabolites, Antineoplastic; Area Under Curve; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Fluorouracil; Gastrectomy; Humans; Kidney Failure, Chronic; Male; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Renal Dialysis; Stomach Neoplasms; Tegafur

In a clinical study, a newly developed anticancer drug, TS-1 capsule, which contained tegafur (FT) and 5-chloro-2,4-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase, was orally administered to five gastric cancer patients (patients 1-5). The total area under the plasma FT concentration-time curve in patient 1 was four-fold higher than in other patients. Since cytochrome P450 2A6 (CYP2A6) has been reported to metabolize FT to yield 5-fluorouracil (5-FU), it was postulated that the poor metabolic phenotype of patient 1 was caused by mutations of the CYP2A6 gene. Thus, alleles for the CYP2A6 genes derived from patient 1 were completely sequenced. It was found that one allele was CYP2A6*4C, which was a whole deleted allele for the human CYP2A6 gene. The other allele was a novel mutant allele (CYP2A6*11) in which thymine at nucleotide 670 was changed to cytosine. The nucleotide change caused an amino acid change from serine at residue 224 to proline. To examine whether or not the amino acid change affected CYP2A6 activity, we expressed an intact or mutant CYP2A6 together with NADPH-P450 oxidoreductase in Escherichia coli, and compared the capacity of the wild and mutant enzymes to metabolize FT to 5-FU. The Vmax value for FT metabolism by the mutant CYP2A6 was approximately one-half of the value of the intact CYP2A6, although the Km values were nearly the same. From these results, we conclude that the poor metabolic phenotype of patient 1 was caused by the existence of the two mutant alleles, CYP2A6*4C and the new variant CYP2A6*11.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Coumarins; Cytochrome P-450 CYP2A6; DNA Primers; DNA, Neoplasm; Drug Combinations; Escherichia coli; Genotype; Humans; Kinetics; Middle Aged; Mixed Function Oxygenases; Mutagenesis, Site-Directed; Oxonic Acid; Polymerase Chain Reaction; Polymorphism, Genetic; Pyridines; Recombinant Proteins; Stomach Neoplasms; Tegafur; Transfection

TS-1(S-1) has been developed as a new oral anticancer drug based on the biological modulation of 5-fluorouracil. We treated a patient with highly advanced gastric carcinoma with a new combination chemotherapy of S-1 and low-dose cisplatin. Remarkable tumor reduction was observed after two cycles of this therapy in the primary tumor and metastatic lymph nodes, and the ascites disappeared. This was concluded to be a partial response. The only adverse effect was skin pigmentation of the fingers (grade 1), leading to early timing of operation after chemotherapy. The gastric tumor showed evident invasion to the serosa. Lymph nodes around the stomach were swollen. Peritoneal dissemination was also recognized in the omentum and mesocolon. Total gastrectomy with regional lymph node dissection was performed. Disseminated tumors were all resected. Histological examination showed that no tumor cells were detected in the gastric primary lesion, metastatic lymph nodes or disseminated peritoneal tumors, suggesting pathological complete remission. It was suggested that this regimen could be a potent combined therapy for the treatment of patients with highly advanced gastric carcinoma, and it could be useful as neoadjuvant chemotherapy. Further studies are necessary to evaluate the efficacy of this therapy.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Combinations; Gastrectomy; Gastroscopy; Humans; Male; Middle Aged; Neoadjuvant Therapy; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Stomach Neoplasms; Tegafur; Tomography, X-Ray Computed; Treatment Outcome

An important cytotoxic effect of 5-fluorouracil (5-FU) is the inactivation of thymidylate synthase (TS) (EC 2.1.1.45) activity by the formation of a ternary complex consisting of covalently bound 5-fluorodeoxyuridine 5'-monophosphate (FdUMP), TS and 5,10-methylenetetrahydrofolate (CH2FH4). The gastrointestinal (GI) toxicity of 5-FU is also caused by its phosphorylation in the GI tract. Potassium oxonate (O(XO)) competitively inhibits pyrimidine phosphoribosyltransferase (EC 2.4.2.10), which converts 5-FU to 5-fluorouridine 5'-monophosphate (FUMP) in vitro. In this study the benefits of combining Oxo and tegafur (FT), which is a masked compound of 5-FU, in reducing the GI toxicity of 5-FU and in protecting the activity of TS in the normal GI tissues were evaluated.. We administered orally a preparation of 1 M FT and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) with or without 1 M O(XO) (called S-1 and FT + CDHP, respectively) or vehicle only (control) to rats for ten consecutive days and compared the toxicity, the histopathological findings and the free TS activity in the GI tissues of the treated rats.. During the experimental periods, the signs of toxicity, such as a decrease in body weight, diarrhea and death, were only observed in the rats treated with FT + CDHP. The histopathological findings in the ileum and colon samples from rats treated consecutively with S-1 on day 1, day 4, day 7 and day 10 were less frequent and more mild than in the samples from rats treated with FT + CDHP. Furthermore, the free TS activities in the ileum samples of rats given S-1 and FT + CDHP were significantly decreased compared with the activity in samples from the control rats throughout the experimental periods. The free TS activities in GI tissues of rats treated with S-1 were higher than the TS activities in tissues from rats treated with FT + CDHP daily from day 4 to day 10, although activities in S-1-treated rat were decreased to almost same low levels as in FT + CDHP-treated rats on day 1.. Our results suggest that repeated simultaneous administration of Oxo and FT can effectively protect the activity of TS by decreasing FdUMP via FUMP from 5-FU in GI tissue, and may lead to a reduction in GI toxicity.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Colon; Diarrhea; Digestive System; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Fluorodeoxyuridylate; Fluorouracil; Ileum; Male; Oxonic Acid; Pyridines; Rats; Tegafur; Thymidylate Synthase

A high-performance liquid chromatography (HPLC) and gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICI-MS) method was developed for the analysis of the combined antitumor drug S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate) and active metabolite 5-fluorouracil in human plasma and urine. Tegafur was fractionated from biological fluids by extraction with dichloromethane and analyzed by HPLC. 5-Fluorouracil and 5-chloro-2,4-dihydroxypyridine were extracted with ethyl acetate from the residual layer after extraction of tegafur, and converted to pentafluorobenzyl (PFB) derivatives. Potassium oxonate was cleaned up with an anion-exchange column (Bond Elut NH2). The extracted potassium oxonate was degraded to 5-azauracil and converted to PFB derivatives. The PFB derivatives were analyzed by GC-NICI-MS. A stable isotope was employed as the internal standard in the GC-NICI-MS analysis. The limits of quantitation of tegafur, 5-fluorouracil, 5-chloro-2,4-dihydroxypyridine and potassium oxonate in plasma were 10, 1, 2 and 1 ng/ml, respectively. The reproducibility of the analytical method according to the statistical coefficients is approximately 10%. The accuracy of the method is good; that is, the relative error is < 10%. The methods were applied to pharmacokinetic studies of S-1 in patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chromatography, High Pressure Liquid; Drug Combinations; Drug Stability; Fluorouracil; Gas Chromatography-Mass Spectrometry; Humans; Hydrogen-Ion Concentration; Kinetics; Magnetic Resonance Spectroscopy; Oxonic Acid; Pyridines; Sensitivity and Specificity; Tegafur

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, the single-dose toxicity of S-1 as well as that of its components, CDHP and Oxo, was investigated in mice, rats, and dogs. The following results were obtained. 1. In mice and rats, excretion of diarrheal stools, salivation, and alopecia were observed after S-1 administration. In severe cases, the animals subsequently showed emaciation due to weight loss or suppressed weight gain, decreased spontaneous motor activity, an anemic appearance, bradypnea, prone position, and death. In the CDHP and Oxo treatment groups of rats, the only toxic signs were soft or diarrheal stools on the dosing day. 2. In dogs, vomiting and excretion of diarrheal, mucous, or soft stools was observed after S-1 administration. In the CDHP and Oxo treatment groups, excretion of soft and diarrheal stools and vomiting were observed relatively frequently from the dosing day until day 1. 3. In the pathological examination of the animals given S-1, mice and rats showed pulmonary congestion/edema, dark red discoloration of the mesenteric lymph nodes, atrophy of lymphatic tissues such as the thymus and lymph nodes, decreases of lymphocytes in the splenic white pulp and mesenteric lymph nodes, a decrease in bone marrow cells, congestion of the glandular stomach, and aggregates of bacteria in the lung, liver, or spleen. In dogs, abnormal changes were observed mainly in the lymphatic organs such as the thymus and lymph nodes. 4. The LD50 values of S-1 in terms of the amount FT they contained were estimated to be 549 mg/kg for mice(male), 441-551 mg/kg for rats (both sexes) and about 53 mg/kg for dogs (male). The LD50 values of CDHP and Oxo were 2000 mg/kg or higher for both rats (both sexes) and dogs (male). 5. Hematopoietic and lymphatic impairments, immunosuppression associated with respiratory were considered to be the cause of death from S-1. The toxicity of S-1 reflects the toxicity of 5-FU and was not found the different toxicity by the addition of CDHP and Oxo.

Topics: Administration, Oral; Alopecia; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Diarrhea; Dogs; Drug Combinations; Female; Lethal Dose 50; Lymph Nodes; Male; Mice; Motor Activity; Oxonic Acid; Pyridines; Rats; Salivation; Spleen; Survival Rate; Tegafur; Thymus Gland

S-1 is a new antineoplastic agent of a fluorinated pyrimidine derivative containing tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1 with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) and reducing its dose-limiting gastrointestinal toxicity. As a part of the safety evaluation of S-1, reverse mutation tests using bacteria and chromosomal aberration tests using cultured cells, CHL/IU, were conducted to test the in vitro mutagenicity of S-1, CDHP and Oxo. All S-1 doses are expressed as the content of FT. 1. The reverse mutation tests were carried out on S-1 at 1.02-520 micrograms/plate, on CDHP at 39.1-5000 micrograms/plate, and on Oxo at 78.1-5000 micrograms/plate using Salmonella typhimurium strains TA100, TA1535, TA98, and TA1537 and Escherichia coli WP2uvrA. None of the test compounds induced a significant increase over solvent controls in the number of mutant colonies in any tester strains in either system, with or without mammalian metabolic activation (S9 Mix). 2. For the in vitro chromosomal aberration tests, Chinese hamster lung cells (CHL/IU), were treated with S-1 at 27.5-220 micrograms/ml for 24 hr or at 6.88-27.5 micrograms/ml for 48 hr without S9 Mix, and at 110-880 micrograms/ml with S9 Mix, with CDHP at 365-1460 micrograms/ml (10 mM), and with Oxo at 122-1950 micrograms/ml (10 mM), with and without S9 Mix. S-1 with and without S9 Mix, and Oxo only for 48 h treatment without S9 Mix, induced chromosomal aberrations, while CDHP did not. 3. The present study indicates that S-1 was nonmutagenic in bacteria, but clastogenic in vitro. CDHP had no in vitro mutagenic or clastogenic activity. Oxo was positive in the in vitro chromosomal aberration test, but negative in the reverse mutation test.

Topics: Animals; Antimetabolites, Antineoplastic; Biotransformation; Cells, Cultured; Chromosome Aberrations; Cricetinae; Drug Combinations; Escherichia coli; Mutagenicity Tests; Oxonic Acid; Pyridines; Salmonella typhimurium; Tegafur