s-1-(combination) and Neoplasms

We performed a meta-analysis of the risk of oral and gastrointestinal (GI) mucosal injury associated with S-1-based regimens.. Randomized phase II and III trials of patients with solid tumors on S-1; describing events of all-grade and high-grade stomatitis and diarrhea constituted the eligible studies.. After exclusion of ineligible studies, a total of 26 clinical trials were considered eligible for the meta-analysis. The odds ratio (OR) of all-grade and high-grade stomatitis for S-1 vs. non-fluoropyrimidine controls was 4.39 [95% CI: 1.05, 18.37; p = 0.04] and 5.64 [95% CI: 1.46, 21.77; p = 0.01], respectively; while the OR of all-grade and high-grade stomatitis for S-1 vs. infusional 5-fluorouracil (5-FU) control was -1.01 [95% CI: 0.22, 4.63; p = 0.99] and 0.32 [95% CI: 0.20, 0.49; p < 0.00001], respectively. The OR of all-grade and high-grade diarrhea for S-1 vs. non-fluoropyrimidine controls was 2.48 [95% CI: 2.12, 2.90; p < 0.00001] and 1.95 [95% CI: 1.29, 2.96; p = 0.002], respectively; while the OR of all-grade and high-grade diarrhea for S-1 vs. infusional 5-FU control was -1.03 [95% CI: 0.87, 1.22; p = 0.76] and 2.52 [95% CI: 1.80, 3.52; p < 0.00001], respectively.. Compared to non-fluoropyrimidine control, patients treated with S-1-based regimens have an increased risk of all-grade and high-grade stomatitis and diarrhea; while on the other hand, patients treated with infusional 5-FU have a greater risk of high-grade stomatitis and diarrhea compared to patients treated with S-1-based regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Drug Combinations; Fluorouracil; Humans; Intestinal Mucosa; Mouth Mucosa; Neoplasms; Oxonic Acid; Randomized Controlled Trials as Topic; Stomatitis; Tegafur

We performed a meta-analysis oriented at the risk of leucopenic complications associated with S-1-based regimens.. The studies that were granted eligibility for inclusion include randomized phase II and III trials of patients with solid tumors on S-1; that entailed details of events of febrile neutropenia, all-grade and high-grade neutropenia and leucopenia.. After rejecting ineligible studies, a total of 28 clinical trials were elected eligible for further quantitative analysis. The RR of febrile neutropenia, all-grade and high-grade neutropenia for S-1 vs.non fluoropyrimidine controls was 0.27 [95% CI 0.16, 0.46; P < 0.0001] 0.69 [95% CI 0.58, 0.81; P < 0.00001] and 0.47 [95% CI 0.32, 0.70; P = 0.0002], correspondingly; while The RR of all-grade and high-grade leucopenia for S-1 vs.non fluoropyrimidine controls was 0.60 [95% CI 0.46, 0.79; P = 0.0002] and 0.34 [95% CI 0.14, 0.79; P = 0.01], respectively.. The risk of febrile neutropenia, all-grade and high-grade neutropenia and leucopenia is less in S-1-based therapy than in non fluoropyrimidine regimens; yet comparable to the risk associated with infusional 5FU or capecitabine-based regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Combinations; Humans; Neoplasms; Neutropenia; Oxonic Acid; Pyrimidines; Randomized Controlled Trials as Topic; Risk; Tegafur

  Cytotoxic anticancer drugs are the most challenging therapeutic agents among all medicines with relatively narrow efficacy profiles. Therefore, medical oncologists have to practically manage the risk of severe toxic effects to optimize treatment outcomes. Dose and treatment-schedule recommendations for cytotoxic anticancer agents are determined on the basis of clinical trials. Patients enrolled in clinical trials are those likely to receive the drug in clinical practice, excluding those with conditions such as organ dysfunction, obesity, advanced age, or comorbidity. On the other hand, the 'real world' includes large numbers of such patients who do not meet the eligibility criteria of clinical trials. However, there is a paucity of data from sufficiently powered pharmacokinetic and pharmacodynamic studies to support dosage recommendations in such patients. Consequently, dose levels and treatment schedules for chemotherapy in these subjects are somewhat arbitrary and not evidence-based. Pharmacokinetic and pharmacodynamic studies of patients in the 'real world' are needed to address this issue. In this review article, we describe general aspects of clinical pharmacology in cancer patients enrolled in clinical trials and those in the 'real world,' and introduce recent findings regarding the pharmacokinetic and pharmacodynamic properties of irinotecan and S-1 in 'real world' cancer patients.

Topics: Age Factors; Antineoplastic Agents; Camptothecin; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Humans; Irinotecan; Neoplasms; Obesity; Oxonic Acid; Patient Selection; Polypharmacy; Renal Insufficiency; Tegafur

5-FU is a core anticancer agent for GI and other malignancies, and infusional 5-FU regimens have been widely utilized. Orally administrable fluoropyrimidine prodrugs have been developed to enhance the anticancer efficacy of 5-FU and to reduce its adverse reactions.. S-1 is an FT-based oral 5-FU prodrug in combination with a DPD inhibitor (CDHP) and an OPRT inhibitor (Oxo), which exerts the following effects: i) maintaining normal gut immunity, Oxo can decrease GI toxicities of 5-FU; ii) sustaining high plasma 5-FU concentrations, Cmax of FBAL after S-1 administration is extremely low, which dramatically decreases adverse reactions such as HFS, neurotoxicities and cardiotoxicities; iii) plasma 5-FU concentrations vary less extensively after S-1 administration and iv) S-1 can be safely administered to patients with DPD deficiency. Furthermore, the alternate-day S-1 administration can reduce the GI toxicities and myelotoxicities of 5-FU without reducing its anticancer efficacy, enabling patients to continue the oral administration for 6 - 12 months.. Replacement of regimens with infusional 5-FU and other fluoropyrimidines by the alternate-day S-1 administration may be recommended because the latter procedure is efficient for patients while sustaining the enhanced anticancer efficacy of 5-FU and without reducing its dose intensity.

Topics: Absorption; Administration, Oral; Antimetabolites, Antineoplastic; Area Under Curve; Drug Administration Schedule; Drug Combinations; Humans; Molecular Structure; Neoplasms; Oxonic Acid; Prodrugs; Tegafur

S-1 is an oral fluoropyrimidine that is designed to improve the antitumor activity of 5-fluorouracil (5-FU) concomitantly with an intent to reduce its toxicity. S-1 consists of tegafur, a prodrug of 5-FU combined with two 5-FU biochemical modulators:5-chloro-2,4-dihydroxypyridine (gimeracil or CDHP), a competitive inhibitor of dihydropyrimidine dehydrogenase and oteracil potassium which inhibits phosphorylation of 5-FU in the gastrointestinal tract decreasing serious gastrointestinal toxicities,including nausea, vomiting, stomatitis and diarrhea. Being an oral agent, S-1 offers convenience of administration and prevents complications of central venous access such as infection, thrombosis and bleeding. S-1 has shown efficacy in both gastrointestinal as well non-gastrointestinal malignancies. The authors review the current literature and provide their expert opinion on the incorporation of S-1 in the treatment of solid malignancies [corrected].

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Combinations; Drug Evaluation, Preclinical; Humans; Neoplasms; Oxonic Acid; Tegafur

C. Heidelberger et al left great gifts to us. Approximately 50 years have elapsed since their discovery of 5-FU in 1957 before eventually elucidating the mechanisms by which the drug exerts its pharmacological actions and provokes its adverse reactions. Namely, 5-FU is a typical antimetabolite with strong time dependency, and continuous venous infusion(CVI) is considered to be its optimal regimen. The following facts may be mentioned to explain why such a long period of time has been spent to reach this level of research: 1) 5-FU, when administered to the living individual, is mostly inactivated by hepatic catabolic enzymes without delay and is then excreted in the urine, thus making it difficult to precisely analyze the relationship of blood 5-FU concentrations with concentration persistence, anticancer activity, and adverse reactions; and 2) unlike other anticancer agents, an antimetabolite 5-FU separately generates metabolites which show anticancer activity and adverse reactions, as well as metabolites which show adverse reactions only. For the last 30 years, we paid attention especially to 5-FU among chemotherapeutic agents for cancer and have sought for a long-lasting therapeutic modality which maintains quality of life of the patient and patient compliance by considering the balancing between its effects and adverse reactions. Consequently, we concretized an innovative therapeutic drug, TS-1 (S-1). We have a long history of research before developing S-1, which is represented by a series of investigations consisting in the developments of Futrafur (FT)--an oral anticancer agent of a 5-FU derivative (prodrug)-in 1970 subsequent to the above discovery of 5-FU, of UFT(FT: Ura=1 : 4) in 1976, and of S-1 in 1999. To date, we took the initiative in the world to devise S-1, the first self-rescuing concept(SRC)-based anticancer agent with dual actions, i.e., enhancement of pharmacological actions of 5-FU and reduction of its adverse reactions, by making use of the biochemical and enzymological properties of 5-FU and by combining FT, which is gradually converted to 5-FU in the body, with a 5-FU's effect-enhancing substance and a 5-FU's adverse reaction-reducing substance. S-1 is an oral anticancer agent in capsule, in which the following 2 modulators for 5-FU are combined to FT: one is CDHP(5-chloro-2,4-dihydroxypyridine) which increases blood concentrations and enhances pharmacological actions of 5-FU by potently inhibiting the degradation of 5-FU; and anot

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Drug Administration Schedule; Drug Combinations; Drug Synergism; Fluorouracil; Humans; Neoplasms; Oxonic Acid; Pharmaceutical Preparations; Prodrugs; Tegafur

S-1 is an attractive oral fluorouracil antitumor drug, which is being called "a self-rescuing drug". This novel oral fluoropyrimidine is combined with three pharmacological agents: tegafur (FT) which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) activity, and potassium oxonate (Oxo) which reduces gastrointestinal toxicity. Phase I and an early phase II clinical trials were performed about ten years ago, and these results had already been introduced to the Journal "Clinical Cancer Research Vol. 5, pages 2000-2005, 1999". The data of this article in this journal was referred from the results of the figures and tables based on the above trial. Most of the authors in this article have contributed on that pharmacokinetics study and published the above manuscripts. In that study, the pharmacokinetics of 5-FU, intact FT, CDHP and Oxo after administration of the standard dose of S-1 had been performed. These studies were carried out at two hospitals, Department of Surgery (Section 1) Sapporo Medical University and Chemotherapy Cancer Center, Cancer Institute Hospital and Japanese Foundation for Cancer Research (Ohtsuka). The number of patients accepted for this trial is twelve, 5 patients with gastric cancer, 4 with colorectal cancer and 3 with breast cancer. Single administration trial was referred to all patients, but consecutive administration trial was limited to ten patients. The results of plasma concentration, Cmax, Tmax, AUC0-14, and T1/2 of 5-FU, FT, CDHP, and Oxo were ascertained in details. It was a surprise that the indicated data was very similar to that of the intravenous 5-FU continuous infusion. Therefore, the low dose administration of 5-FU (FT) as S-1 may result in good antitumor effects with minimum adverse effects to the patients.

Topics: Administration, Oral; Adult; Aged; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Female; Fluorouracil; Humans; Kidney; Male; Middle Aged; Neoplasms; Oxonic Acid; Rats; Tegafur; Uracil

Lentinan is a beta(1-3) glucan clarified to have a life prolonging effect in non-operable, recurrent gastric cancer patients in combination with chemotherapy. The long lasting issue remaining to be resolved has been the ineffectiveness of Lentinan when administered per-orally. Beta(1-3) glucans possess the particulate size around 100-200 microm in aqueous solution which dampered the absorption through abdominal mucosa. Subsequently the particulate size of Lentinan impaired the immunostimulating potency, to induce reductive form of antigen presenting cells, macrophages and dendritic cells relevant for the polarization of Th1/Th2 balance to Th1. The situation is also the case for the clinical benefit of lentinan to reduce the side effect of chemotherapeutic agents such as TS-1, Gemzar, CDDP, known to be a critical dose limiting factor of these agents and to improve quality of life of the patients. Using the modern nano-technology procedures, Mitherapist, containing 15 mg/dl Lentinan, with a particulate size of 0.2 microm able to pass through mucosal barrier was provided. It was found in randomized double blind clinical testing that Mitherapist is effective against allergy by reducing an antigen specific IgE level through polarization to Th1 biased immune response even by per-oral administration. Per oral administration also exhibited the reduced side effect of chemotherapeutic agents such as TS-1, Gemzar, CDDP and greatly improved quality of life of the cancer patients. The role of hypoxia in local neoplastic tissues will be also discussed.

Topics: Adjuvants, Immunologic; Administration, Oral; Antineoplastic Agents; beta-Glucans; Drug Combinations; Humans; Immunotherapy; Lentinan; Neoplasms; Oxonic Acid; Pyridines; Randomized Controlled Trials as Topic; Stomach Neoplasms; Tegafur

For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inh

Topics: Animals; Antineoplastic Agents; Apoptosis; Capecitabine; Cell Cycle; Cell Proliferation; Clinical Trials as Topic; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Leucovorin; Neoplasms; Oxonic Acid; Prodrugs; RNA, Messenger; Tegafur; Thymidylate Synthase

Topics: ADP Ribose Transferases; Animals; Antineoplastic Agents; Benzamides; Cisplatin; Drug Combinations; Fluorouracil; Genes, ras; Humans; Imatinib Mesylate; Insect Proteins; Lung Neoplasms; Mice; Neoplasms; Neoplastic Syndromes, Hereditary; Oxonic Acid; Piperazines; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Signal Transduction; Tegafur; Tumor Cells, Cultured

Researchers, primarily in Japan, Europe, and the United States, have evaluated several new fluorinated pyrimidines in recent years. Most of these drugs are orally active prodrugs of fluorouracil (5-FU), and some also contain modulators of its pharmacological properties. S-1 is a rationally developed combination of tegafur, a prodrug of 5-FU; CDHP, an inhibitor of 5-FU catabolism; and potassium oxonate, an inhibitor of 5-FU-induced diarrhea. S-1 underwent phase I and II trials in Japan, where it is now approved for use in the treatment of advanced gastric cancer. Two phase I studies conducted recently in Europe and the United States identified diarrhea as the dose-limiting toxicity of S-1. BOF-A2, which contains a 5-FU prodrug and CNDP, an inhibitor of 5-FU catabolism, demonstrated clinical activity in preliminary studies in Japan. This article summarizes the preclinical and clinical development of S-1 and BOF-A2.

Topics: Antimetabolites, Antineoplastic; Clinical Trials as Topic; Drug Combinations; Fluorouracil; Humans; Neoplasms; Oxonic Acid; Pyridines; Tegafur

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the (fluoro) pyrimidine catabolic pathway, and has an important role in 5-fluorouracil (5-FU) pharmacology. Some studies have demonstrated that the fluoropyrimidine catabolite may be related to the toxicity of 5-FU, and tumoral DPD prescribes the response to 5-FU-based therapy. By controlling DPD activity, a new class of fluorinated pyrimidines have been developed to minimize the variability of 5-FU pharmacodynamics, to decrease 5-FU toxicity, and improve its efficacy. Recently, these drugs, referred to as DIFs (DPD inhibitory fluoropyrimidines), have brought us to a new era of oral 5-FU therapy. The importance of DIF in 5-FU-based therapy is reviewed herein.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Fluorouracil; Humans; Neoplasms; Oxidoreductases; Oxonic Acid; Pyridines; Tegafur; Uracil

Protracted intravenous regimens of fluorouracil (5-FU) may be superior and better tolerated than intravenous bolus dosing. An effective oral regimen would allow a protracted course of 5-FU without the need for central venous lines and the associated increase in complications. Approximately 85% of 5-FU is degraded by dihydropyrimidine dehydrogenase (DPD); inhibition of this enzyme pathway can increase the amount of circulating 5-FU. Two oral fluoropyrimidines commonly referred to as DPD inhibitory fluoropyrimidines, or DIFs, UFT plus leucovorin (LV) and S-1 are reviewed herein. These agents represent an approach to more convenient, less toxic 5-FU therapy. In two multicenter, randomized, phase III trials in patients with advanced colorectal cancer, UFT/LV produced equivalent activity compared with intravenous 5-FU/LV but with significantly less major toxicity. The predominant side effect of UFT, diarrhea, is generally self-limited and easily managed. Myelosuppression and hand-foot syndrome were rarely noted in the schedules used in these trials. S-1 has demonstrated promising activity in phase II trials conducted in patients with gastric, colorectal, breast, and head and neck cancers. Ongoing trials are defining the roles of these agents in a variety of malignancies.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Humans; Leucovorin; Neoplasms; Oxidoreductases; Oxonic Acid; Pyridines; Radiation-Sensitizing Agents; Tegafur; Uracil

Four fluorinated pyrimidines that are in the stage of clinical trials at present in Japan were reviewed: BOF-A2, Ro09-1390, TT-62 and S-1. Both BOF-A 2 and S-1 are a compound of 5-FU derivative combined or mixed with an inhibitor of 5-FU degradation in order to prolong the blood 5-FU level as well as increase selective toxicity to tumor. Furthermore, an inhibitor of 5-FU phosphorylation in G1 tract contained in S-1 reduces G1 toxicity such as diarrhea etc due to prolongation of blood 5-FU level. Ro09-1390 is an improved compound of 5'-DFUR, which intends to reduce diarrhea caused by the latter. TT-62 is a FdUMP derivative and an active metabolite of 5-FU for oral formulation, which is superior to available 5-FU type anticancer agents in efficacy, and doesn't show cross tolerance to 5-FU.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Deoxycytidine; Drug Combinations; Fluorodeoxyuridylate; Fluorouracil; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasms; Neoplasms, Experimental; Oxonic Acid; Pyridines; Rats; Tegafur

Topics: Aged; Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Drug Combinations; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Nomograms; Oxonic Acid; Renal Insufficiency; Tegafur

S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1.. A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m(2), po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, t1/2, AUC0-t, and AUC0-∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and Cmax of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews.. The mean values of Cmax, AUC0-t, and AUC0-∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found.. The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m(2)) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asian People; Cross-Over Studies; Drug Combinations; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Tegafur; Therapeutic Equivalency

S-1 is a novel oral fluoropyrimidine comprised of FT and two modulators, gimeracil (CDHP) and oteracil potassium (Oxo). This study investigated the food effects on the pharmacokinetics (PK) of Oxo, other components of S-1, and their metabolites at different gastric pH adjusted by proton pump inhibitor (PPI).. Patients with and without PPI were treated with S-1 at 30 mg/m(2) twice daily orally on days 1-7 under either fed or fasting condition, and then were crossed over to fasting/fed conditions on days 15-21 with washout on days 8-14 and 22-28.. The study enrolled 55 patients including 27 PK-evaluable patients. For the single-dose and multiple-dose pharmacokinetics, the administration of S-1 under fed conditions resulted in decreased exposure to Oxo relative to fasting administration. There was a marginal decrease in exposure to CDHP and 5-FU under fed versus fasting conditions, although FT exposure was not altered by food, which demonstrated lack of food effect. PPI administration together with S-1 did not significantly change its bioavailability.. Oxo exposure was reduced under fed compared to fasting condition. To increase the bioavailability of S-1, the administration of S-1 under fasting condition was more effective in the western countries.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Biological Availability; Cross-Over Studies; Drug Administration Schedule; Drug Combinations; Fasting; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Proton Pump Inhibitors; Tegafur; Treatment Outcome

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

S-1 is a novel oral agent combining the 5-fluorouracil (FU) prodrug tegafur with gimeracil and oteracil, which inhibit 5-FU degradation by dihydropyrimidine dehydrogenase and phosphorylation within the gastrointestinal tract, respectively. The study was designed to identify the maximum tolerable dose and the dose-limiting toxicities of two schedules of S-1 combined with oxaliplatin and bevacizumab, in advanced solid tumor patients.. Schedule A: S-1 was administered orally at 20 mg/m(2) twice daily for 14 consecutive days, escalated by 5 mg/m(2), with fixed-dose intravenous bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) on day 1 of each 3-week cycle. Schedule B: S-1 was administered at 25 mg/m(2) twice daily for 7 consecutive days, escalated by 5 mg/m(2), with fixed-dose intravenous bevacizumab 5 mg/kg and oxaliplatin 85 mg/m(2) on day 1 of each 2-week cycle.. The maximum tolerated dose and recommended phase II dose of S-1 was 25 mg/m(2) twice daily for 14 days for schedule A and 35 mg/m(2) twice daily for 7 days for schedule B. The most common dose-limiting toxicities were grade 3 diarrhea. Both regimens were well tolerated. No pharmacokinetic interactions between oxaliplatin and S-1 components were observed.. S-1, oxaliplatin and bevacizumab can be administered with acceptable safety and tolerability and without evidence of pharmacokinetic interactions.

Topics: Administration, Oral; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Drug Combinations; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

We developed a population pharmacokinetic (PPK) model of S-1 including the cytochrome P450 (CYP) 2A6 genotype and then used this PPK model to assess the influence of the CYP2A6 genotype on PK parameters of S-1 and the relationship between toxicity and the individual maximum concentrations (Cmax) or the area under the concentration-time curve (AUC) of 5-fluorouracil (5-FU) in Japanese patients with advanced cancer. Fifty-eight patients with advanced cancer were assessed. A dose of 80 mg/m(2)/day of S-1 was given orally. On the basis of the CYP2A6 genotypes (*1, *4, *7 and *9), all patients were classified as having the wild-type, 1 variant allele or 2 variant alleles. The PPK model was established with plasma concentration data for tegafur (FT), 5-chloro-2,4-performed dihydroxypyridine (CDHP) and 5-FU. In patients with 2 variant alleles of CYP2A6, the clearance of FT was 58% less than in patients with the wild-type or 1 variant allele. The AUC of 5-FU correlated with the AUC of CDHP, but not with the AUC of FT. Therefore, the CYP2A6 genotype did not affect the AUC of 5-FU. The individual AUC or Cmax of 5-FU did not differ significantly between patients with grade 3 or 4 toxicities and patients with grade 0-2 toxicities. In conclusion, the CYP2A6 genotype did not affect the AUC of 5-FU, although the clearance of FT was lower in patients with 2 variant alleles of CYP2A6 than in patients with the wild-type or 1 variant allele.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Asian People; Cytochrome P-450 CYP2A6; Disease Progression; Drug Combinations; Female; Fluorouracil; Genotype; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Oxonic Acid; Pharmacogenetics; Tegafur

S-1 is an oral anticancer agent that combines tegafur (FT) with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate. The recommended initial dose of S-1 is 120 mg/day for patients with a body surface area (BSA) of > or =1.5 m(2) in Japan.. We examined the effects of using this fixed dose on the pharmacokinetics of FT, CDHP, and active 5-fluorouracil (5-FU) on the basis of actual BSA. The pharmacokinetics was compared between patients with a BSA of 1.5-1.75 m(2) and those with a BSA of > or =1.75 m(2).. The median areas under the time-concentration curves (AUCs) of 5-FU and CDHP were significantly lower in patients with a BSA of > or =1.75 m(2) than in those with a BSA of 1.5-1.75 m(2) (P = 0.005 and 0.006, respectively; Mann-Whitney U-test). There was no difference between the groups in the median AUC of FT.. Systemic exposure to 5-FU is significantly lower in Japanese cancer patients with a large BSA of >1.75 m(2) who received the recommended fixed dose of S-1.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Area Under Curve; Body Surface Area; Drug Combinations; Drug Dosage Calculations; Female; Humans; Japan; Male; Middle Aged; Neoplasms; Oxonic Acid; Tegafur; Treatment Outcome

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

S-1 is an oral formulation of ftorafur (FT), oxonic acid and 5-chloro-2,4-dihydroxypyridine (CDHP) at a molar ratio of 1:0.4:1. FT is a 5-fluorouracil (5-FU) prodrug, CDHP is a dihydropyrimidine dehydrogenase (DPD) inhibitor and oxonic acid is an inhibitor of 5-FU phosphoribosylation in the gastrointestinal mucosa and was included to prevent gastrointestinal toxicity. We determined the pharmacokinetics of S-1 in 28 patients at doses of 25, 35, 40 and 45 mg/m(2). The plasma C(max) values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1-2 h were in the ranges 5.8-13 microM, 0.4-2.4 microM, 0.026-1.337 microM, and 1.1-3.6 microM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03-0.25 microM to 3.6-9.4 microM after 2-4 h, and 0.09-0.9 microM was still present after 24 h. The pharmacokinetics of CDHP and uracil were linear over the dose range. The areas under the plasma concentration curves (AUC) for CDHP and uracil were in the ranges 418-1735 and 2281-8627 micromol x min/l, respectively. The t(1/2) values were in the ranges 213-692 and 216-354 min, respectively. Cumulative urinary excretion of FT was predominantly as 5-FU and was 2.2-11.9%; the urinary excretion of both fluoro-beta-alanine and uracil was generally maximal between 6 and 18 h. During 28-day courses with twice-daily S-1 administration, 5-FU and uracil generally increased. Before each intake of S-1, 5-FU varied between 0.5 and 1 microM and uracil was in the micromolar range (up to 7 microM), indicating that effective DPD inhibition was maintained during the course. In a biopsy of an esophageal adenocarcinoma metastasis that had regressed, thymidylate synthase, the target of 5-FU, was inhibited 50%, but increased four- to tenfold after relapse in subsequent biopsies. In conclusion, oral S-1 administration resulted in prolonged exposure to micromolar 5-FU concentrations due to DPD inhibition, and the decrease in uracil levels after 6 h followed the pattern of CDHP and indicates reversible DPD inhibition.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Drug Combinations; Female; Fluorouracil; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Tegafur; Tissue Distribution; Uracil

To determine the maximum tolerated dose, dose-limiting toxicities(DLTs), and pharmacokinetics of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oxonic acid, administered once daily in patients with advanced cancer.. Eighteen patients with refractory malignancies were treated with S-1 administered once daily for 21 consecutive days, followed by a 1-week break. Of 16 evaluable patients, 6 were treated at a dose of 50 mg/m(2)/day, and 10 were treated at 60 mg/m(2)/day.. DLTs were observed in 1 of 6 evaluable patients treated with 50 mg/m(2)/day and in 4 of 10 evaluable patients treated with 60 mg/m(2)/day. DLTs included diarrhea, nausea/vomiting, fatigue, and hyperbilirubinemia. The maximum tolerated dose was 50 mg/m(2)/day. Pharmacokinetic data are consistent with potent modulation of 5-fluorouracil (5-FU) by CDHP, with prolonged half-life and 5-FU AUC at least 10-fold higher than reported in previous studies of equitoxic doses of tegafur modulated by uracil. Pharmacodynamic analysis demonstrated a correlation between diarrhea grade and both 5-FU C(max) (r = 0.57, P < 0.05) and 5-FU area under the curve (r = 0.74, P < 0.01).. The recommended Phase II dose of S-1 administered once daily for 21 consecutive days of 28 is 50 mg/m(2). The pharmacokinetic data presented provide evidence of 5-FU modulation by CDHP. Pharmacodynamic analyses suggest that the utility of pharmacology-based dosing of S-1 should be explored in future trials. Evaluation of once-daily dosing of S-1 in malignancies for which fluoropyrimidines have known antitumor activity is warranted.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Area Under Curve; Drug Administration Schedule; Drug Combinations; Female; Gastrointestinal Diseases; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Tegafur

To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate.. Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter.. Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU.. The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Tegafur

S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Breast Neoplasms; Colorectal Neoplasms; Drug Combinations; Drug Evaluation; Female; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

We have conducted Phase I study of a novel oral antitumor agent of fluorinated pyrimidines, S-1, in which tegafur (FT) is combined with two classes of modulator, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT:CDHP:Oxo = 1:0.4:1 as a multi-center study with 16 institutions nationwide. Two administration methods, once and twice daily administrations, were evaluated. As a result, MAD was determined as 150 mg/body/day approximately 200 mg/body/day and 75 mg/body x2/day approximately 100 mg/body x2/day, respectively. DLF was myelosuppression, mainly consisting of leukopenia in the two administrations. Most adverse reactions observed, including myelosuppression, disappeared by discontinuation of administration, and recovery was in about 2 weeks. Adverse reactions other than myelosuppression which induced the discontinuation were rash and vomiting. Other adverse reactions observed were anorexia, malaise, diarrhea and stomatitis. Diarrhea and stomatitis were mild (Grade 1), except those observed at a dose of 200 mg/body/day, and did not induce discontinuation of administration. Based on these findings and pharmacokinetic evaluation, the recommended dose and administration for Early Phase II studies were determined as twice daily administration of 75 mg/body for 28 consecutive days with 14 days rest (1 course).

Topics: Administration, Oral; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Tegafur

Topics: Antineoplastic Agents; Dihydropyrimidine Dehydrogenase Deficiency; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Fluorouracil; Genotype; Humans; Neoplasms; Oxonic Acid; Pharmacogenomic Testing; Phenotype; Point-of-Care Testing; Pyrrolidines; Tegafur; Thymine; Trifluridine; Uracil

Lacrimation is among the typical adverse drug reactions associated with S-1 treatment. However, lacrimation frequencies differ between reports, and a clear consensus regarding reaction times, risk factors, and symptomatic treatment for lacrimation is lacking. We retrospectively investigated the reaction times, risk factors, and outcomes of symptomatic treatment for lacrimation in 202 patients treated with S-1. The median estimated creatinine clearance noted upon initiation of cancer treatment was 75.8mL/min. The median of the relative treatment intensity was 87.1%, while the incidence of lacrimation was 26.7%. The median cumulative dose of S-1 before the onset of lacrimation was 23,520 mg in all patients, and 5,050 mg in those who developed lacrimation. Of the patients who developed lacrimation, 40.7% developed this symptom within 2 months after starting S-1 treatment. There were no apparent risk factors. The most frequently employed symptomatic treatment was a physiological saline ophthalmic solution provided as a hospital preparation. After treatment with this ophthalmic solution, 29.4% of the affected patients showed improvement and 70.6% showed no change; none however, experienced worsening of symptoms. These results suggest that clinicians should assess the presence of lacrimation after starting treatment with S-1. Symptomatic treatment with an ophthalmic solution that does not have a tear retention capacity may be useful in patients who have developed lacrimation.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Drug Combinations; Female; Humans; Lacrimal Apparatus Diseases; Male; Middle Aged; Neoplasms; Oxonic Acid; Retrospective Studies; Tegafur

To establish a method for the measurement of 5-fluorouracil (5-FU), and tegafur (FT) in tear samples from patients treated with oral fluoropyrimidine anticancer agent S-1.. Cross-sectional study.. High performance liquid chromatographic (HPLC) method reported for plasma samples was modified for tear samples. Simulated-tear solutions containing lactoferrin, lysozyme and standard solution containing 5-FU or FT were prepared for preliminary measurements. Tear samples from seven patients treated with S-1 were included. The tears were collected following S-1 administration using Schirmer's strips.. 5-FU and FT concentrations of pure standard solution without extraction process were detected as original concentration. However, on extraction, FT samples in simulated-tear solution showed a peak for 5-FU but not for FT. FT was converted to 5-FU in the extraction process. Decomposition from FT to 5-FU was suppressed when 50 mg/mL bovine serum albumin was added during extraction. The mean concentrations of 5-FU and FT in tears during S-1 treatment were 0.17 ± 0.11 and 1.94 ± 0.71 μg/mL, respectively.. A simple HPLC method to determine 5-FU and FT in tear samples was established.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasms; Oxonic Acid; Tears; Tegafur

S-1 is an oral antineoplastic agent containing tegafur, gimeracil, and oteracil potassium. Recently, ophthalmic disorders, particularly epiphora, have been reported. We retrospectively investigated the incidence of ophthalmic disorders in patients treated with a regimen containing S-1 at our institution. Ophthalmic disorders were noted in 28 of 261 patients(10.7%). These included epiphora(17 cases), eye discharge(10 cases), conjunctivitis(6cases ), blurred vision(3 cases), and eye discomfort(2 cases), as well as eye pain, pruritus, dry eye, hordeolum, and visual loss(1 case each). The median time from starting treatment to appearance of the condition was 3.0(interquartile range 1.5-4.5)months and the median cumulative S-1 dose was 4.2(interquartile range 2.2-9.5)g. More men than women developed ophthalmic disorders on S-1. The median total dose and duration of treatment were higher in those developed ophthalmic disorders than in those who did not (12.4 g vs 6.3g and 8.6 months vs 4.4 months). Epiphora was the most common of a number of ophthalmic disorders seen in our patients treated with S-1. Patients and physicians should be fully informed of the potential association between S-1 and ophthalmic disorders, and patients receiving this treatment need to be carefully monitored.

Topics: Aged; Antimetabolites, Antineoplastic; Drug Combinations; Eye Diseases; Female; Humans; Incidence; Male; Middle Aged; Neoplasms; Oxonic Acid; Retrospective Studies; Tegafur

Topics: Adult; Aged; Aged, 80 and over; Capecitabine; Denmark; Drug Combinations; Drug Substitution; Female; Hand-Foot Syndrome; Humans; Male; Middle Aged; Neoplasms; Netherlands; Oxonic Acid; Retrospective Studies; Tegafur; Treatment Outcome; Western World

Prolonged prothrombin time is observed in patients taking warfarin (WF) with a fluoropyrimidine, such as S-1. When WF is combined with S-1, the prothrombin time-international normalized ratio (PT-INR) and dose adjustment of WF should be closely monitored. To date, no clinical data have been reported in terms of the relation between temporal variation of PT-INR and its therapeutic range. In this study, we retrospectively collected patients' clinical data including PT-INR. We identified 21 patients receiving WF therapy before the start of S-1 treatment. Patient characteristics were male/female: 18/3, median age: 69 (range 48-81) years old, cancer of gastric/lung/pancreatic/other: 8/5/4/4, and history of deep vein thrombosis (DVT)/atrial fibrillation (AF)/cerebral infarction (CI)/other: 11/6/2/2. The PT-INR of 16 patients exceeded normal upper limits after taking S-1 with WF. The median time to exceed the PT-INR upper therapeutic range is 25 (range 3-77) days. Patients receiving WF anticoagulant therapy concomitant with S-1 should have their PT-INR closely monitored and WF doses adjusted accordingly.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antimetabolites, Antineoplastic; Drug Combinations; Drug Interactions; Female; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Prothrombin Time; Retrospective Studies; Tegafur; Warfarin

S-1 (tegafur/gimeracil/oteracil potassium) is an effective oral anticancer drug for treatment of a wide spectrum of cancers. However, it may incur serious adverse effects through factors such as interactions with other drugs, renal dysfunction, or an insufficient washout period. In view of this, pharmacists should play an increasingly significant role in managing the medication history of patients treated with S-1. As there seems to be no standardized management tool for patients receiving S-1, we conducted a retrospective study to evaluate medication history management methods, which are commonly available in community pharmacies as well as hospitals. We identified 128 outpatients who were prescribed S-1 for the first time at the National Cancer Center Hospital from July to December of 2011. These patients were divided into in-hospital (n=48) and out-of-hospital (n=80) groups. The percentage of patients, who dropped out during the first course of S-1 treatment, was 16.7% for the in-hospital group, and 10% for the out-of-hospital group. Examining renal dysfunction, non-elderly patients with low creatinine clearance (Ccr) were found. These results suggest that there is the possibility of side effect occurrence in both the in-hospital and out-of-hospital prescription groups. Community pharmacists should check prescriptions with particular attention to the Ccr. It is necessary to develop mechanisms for cooperation between hospital and community pharmacists, with clear role sharing between them, allowing the community pharmacists to exercise medication history management for patients prescribed S-1 to the same degree as hospital pharmacists based on available information including laboratory test values.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Community Pharmacy Services; Drug Combinations; Female; Health Records, Personal; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Pharmacy Service, Hospital; Professional Role; Retrospective Studies; Tegafur

To identify predictive factors for ocular complications caused by the anticancer drug S-1.. A questionnaire was administered to 39 patients who underwent S-1 chemotherapy at Kobe City Medical Center General Hospital, with the aim to determine whether these patients were aware of the ocular complications caused by S-1. Cognition rate was determined. The 26 patients who requested opthalmological examination for further evaluation studied further and classified into two groups-those who had developed corneal epithelial complications, conjunctival injection or chemosis, or lacrimal duct blockages (referred to as the positive group) and those without these findings (referred to as the negative group). Predictive factors, such as age, sex, total administration days, total dose, presence or absence of anticancer drug pretreatment, and single-drug or combination-drug therapy, were investigated and compared between groups.. Of the 39 patients who completed the questionnaire, ten were aware of the potential for ocular complications due to S-1 chemotherapy (cognition rate 25.6 %). Of the 26 patients who had requested opthalmological examination and entered into the study, 13 (26 eyes) were classified into the positive group, with corneal complications observed in 15 eyes (57.7 %), conjunctivitis in 26 eyes (100 %), and lacrimal duct blockage in 14 eyes (53.8 %). Cognition rate in the 13 patients in the positive group and the 13 patients in the negative group was 38.5 % (5 patients) and 7.7 % (1 patient), respectively. Patient age was significantly different between the two groups, with the patients in the positive group being significantly older than those in the negative group (mean age ± standard deviation: 71.6 ± 6.8 vs. 63.5 ± 7.3 years, respectively; P = 0.0077, Student's t test). No other significant predictive factors were detected.. Older patients were at greater risk of S-1-related ocular complications, but these complications were not associated with total administration days or total dose.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Conjunctivitis; Corneal Diseases; Drug Combinations; Female; Health Knowledge, Attitudes, Practice; Humans; Japan; Lacrimal Duct Obstruction; Male; Middle Aged; Neoplasms; Oxonic Acid; Risk Factors; Surveys and Questionnaires; Tegafur

Topics: Antimetabolites, Antineoplastic; Conjunctivitis; Corneal Diseases; Drug Combinations; Epithelial Cells; Humans; Lacrimal Duct Obstruction; Neoplasms; Oxonic Acid; Tegafur

The elucidation in recent years of intracellular signaling mechanisms related to cancer cell growth has been accompanied by increases in both drug development and biomarker research. While treatment strategies using biomarkers have been established and put to clinical use for various types of cancers and medications, most are limited to drugs targeting specific molecules, and none have been established for traditional cytotoxic drugs. For fluoropyrimidines, the standard drugs used in chemotherapy for gastrointestinal cancer, biomarker research has been conducted on targets such as thymidylate synthase(TS), dihydropyrimidine dehydrogenase(DPD), and thymidine phosphorylase(TP). The results of research on these targets have recently been reported, albeit retrospectively, in a number of additional studies and large-scale clinical trials. While some studies suggested that there is future potential for these targets, in general, it appears that there are insufficient data for their clinical application as biomarkers at present. Given the advances made toward the realization of personalized medicine, the discovery of biomarkers for fluoropyrimidines is of great importance and warrants further study.

Topics: Antimetabolites, Antineoplastic; Capecitabine; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Neoplasms; Oxonic Acid; Prognosis; Tegafur

S-1 is an oral fluoropyrimidine anti-neoplastic agent that is converted by CYP2A6 to 5-fluorouracil (5FU). We prospectively studied the pharmacokinetics and pharmacodynamics of S-1 in two groups of East Asian and Caucasian patients with solid malignancy refractory to standard chemotherapy, or for which 5FU was indicated, to elucidate differences in relation to CYP2A6 genotype and phenotype. S-1 was given orally at 30 mg/m(2) b.i.d. for 14 days every 21 days. Dose normalized AUC(0-48 h) for tegafur (P = 0.05) and gimeracil (P = 0.036) were higher in East Asians; conversely, AUC(0-48 h) of fluoro-β-alanine was higher in Caucasians (P = 0.044). Exposure to 5FU was similar in both groups (P = 0.967). Mean cotinine:nicotine ratio was 54% higher in the Caucasian group (P = 0.03), and correlated with oral clearance of tegafur (r = 0.59; P = 0.002). Grade 3/4 gastrointestinal toxicities were more common in Caucasians than Asians (21%vs 0%). Treatment with S-1 yields no significant difference in 5FU exposure between Caucasians and East Asians.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Asia, Eastern; Asian People; Cytochrome P-450 CYP2A6; Drug Combinations; Female; Genotype; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Phenotype; Tegafur; White People

The main goal of a Phase I dose-finding study is the estimation of the maximal tolerated dose (MTD) from a set of available dose levels. For cytotoxic clinical trials in oncology, it is not unusual to find several phases I studies carried out on a new molecule or procedure. For instance, the molecule Sorafenib (which inhibits particular tyrosine kinase enzymes in several cancers) was used alone in five published clinical trials. Each clinical trial was conducted separately in different indications and the resulting data were never pooled in any way. No attempt was made to synthesize or combine the information from the different studies. For dose-finding studies, the toxicity itself may not be related to disease. Integrating information across several Phase I trials may lead to improved inference on the dose level, or levels, corresponding to the MTD. Under strong assumptions, we will provide more accurate estimates of the MTD. Under no assumptions a pooled analysis will perform no less well than several separate analyzes and, under intermediary assumptions, there still may be scope for gains. A difficulty is that many methods are sequential in nature so that, in order to group findings under a single heading, it is necessary to retrospectively analyze data obtained according to a dynamic sequential design. We propose a solution to this difficulty. The approach is illustrated via two real examples.

Topics: Adult; Aged; Antineoplastic Agents; Benzenesulfonates; Clinical Trials, Phase I as Topic; Computer Simulation; Dose-Response Relationship, Drug; Drug Combinations; Humans; Maximum Tolerated Dose; Meta-Analysis as Topic; Middle Aged; Models, Statistical; Neoplasms; Niacinamide; Oxonic Acid; Phenylurea Compounds; Pyridines; Retrospective Studies; Sorafenib; Tegafur

We report the frequency of lacrimal passage disorder and the outcomes of treatment. This retrospective study was performed on 55 cases that were treated with S-1 for at least 1 month. We asked patients about ocular symptoms. An ophthalmic surgeon examined all patients and diagnosed lacrimal passage disorder in 6 of 55 patients (12. 5%). The mean dose of S- 1 was 10, 300 mg, and the average period to onset of lacrimal passage disorder was 5. 7 months. The causes of epiphora included occlusion/stenosis of lacrimal canaliculus, occlusion of lacrimal puncta and stenosis of nasolacrimal duct. Lacrimal surgery was performed in all 6 patients and epiphora improved. Lacrimal passage disorder may result from systemic treatment of patients with S-1. Symptoms of lacrimal passage disorder improved with early detection and treatment by insertion of a silicone tube.

Topics: Aged; Drug Combinations; Female; Humans; Lacrimal Apparatus Diseases; Male; Middle Aged; Neoplasms; Oxonic Acid; Tegafur

5-Fluorouracil (5-FU) is broadly considered the drug of choice for treating human colorectal cancer (CRC). However, 5-FU resistance, mainly caused by the overexpression of antiapoptotic proteins such as Bcl-2, often leads ultimately to treatment failure. We here investigated the effect of Bcl-2 gene silencing, using small interfering RNA (siRNA) (siBcl-2), on the efficacy of 5-FU in CRC. Transfection of siBcl-2 by a Lipofectamine2000/siRNA lipoplex effectively downregulated Bcl-2 expression in the DLD-1 cell line (a CRC), resulting in significant cell growth inhibition in vitro upon treatment with 5-FU. For in vivo treatments, S-1, an oral formulation of Tegafur (TF), a prodrug of 5-FU, was used to mimic 5-FU infusion. The combined treatment of polyethylene glycol (PEG)-coated siBcl-2-lipoplex and S-1 showed superior tumor growth suppression in a DLD-1 xenograft model, compared to each single treatment. Surprisingly, daily S-1 treatment enhanced the accumulation of PEG-coated siBcl-2-lipoplex in tumor tissue. We propose a novel double modulation strategy in cancer treatment, in which chemotherapy enhances intratumoral siRNA delivery and the delivered siRNA enhances the chemosensitivity of tumors. Combination of siRNA-containing nanocarriers with chemotherapy may compensate for the limited delivery of siRNA to tumor tissue. In addition, such modulation strategy may be considered a promising therapeutic approach to successfully managing 5-FU-resistant tumors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Drug Combinations; Gene Knockdown Techniques; Gene Silencing; Genes, bcl-2; Genetic Therapy; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Oxonic Acid; RNA, Small Interfering; Tegafur; Xenograft Model Antitumor Assays

S-1 is an oral anticancer drug containing tegafur (FT), a pro-drug of fluorouracil, combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate (Oxo), at a molar ratio of 1:0.4:1. CYP2A6 genetic polymorphism and dihydropyrimidine dehydrogenase (DPD) inhibition are important for the antitumor effect of S-1. Exploiting the usefulness of the 2-(13)C-uracil breath test (UrBT) as an indicator of DPD activity, we examined whether the results of CYP2A6 genetic polymorphism analysis and UrBT could be used to predict the antitumor effect of S-1.. Thirty-four patients with advanced or recurrent cancer (15, 16 and 3 with gastric, colorectal and pancreatic cancer, respectively) were orally administered 40 mg/m(2) S-1 twice daily in the morning and evening. Eighteen patients with a complete response (CR)/partial response (PR) (2 with CR, 16 with PR) and 16 with progressive disease (PD) were compared with respect to CYP2A6 genetic polymorphisms (1- vs. 2-allele mutation), UrBT results, and plasma FT and 5-fluorouracil levels at 3 h after S-1 ingestion in the morning.. On multivariate analysis between the CR/PR and PD groups, only the UrBT results was an independent factor of CR/PR to S-1 (95% CI 1.02-1.10).. These results suggest that the anticancer effect of S-1 can be predicted by performing UrBT 3 h after the initial oral S-1 administration.

Topics: Aged; Aged, 80 and over; Alleles; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Breath Tests; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2A6; Drug Combinations; Female; Gas Chromatography-Mass Spectrometry; Genotype; Humans; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Neoplasms; Oxonic Acid; Polymorphism, Genetic; Predictive Value of Tests; Prognosis; Radiopharmaceuticals; Tegafur; Uracil

Topics: Aged; Antimetabolites, Antineoplastic; Corneal Diseases; Drug Combinations; Dry Eye Syndromes; Eyelid Diseases; Female; Humans; Male; Meibomian Glands; Microscopy, Confocal; Middle Aged; Neoplasms; Oxonic Acid; Tegafur

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Cimetidine; Cyclooxygenase 2 Inhibitors; Deoxycytidine; Drug Combinations; Drug Therapy, Combination; Gemcitabine; Humans; Hypertension; Interferon-alpha; Life Style; Neoplasms; Oxonic Acid; Renin-Angiotensin System; Tegafur; Tetrazoles

To elucidate the features of optic lesions in patients with epiphora during S-1 therapy.. Twelve patients with epiphora in 123 patients during S-1 therapy.. Age range was 38-84 years (mean 68.4 years). There were 4 cases in 81 men (5%) and 8 in 42 women (19%). Epiphora occurred significantly more often in women (p=0.02). The administration period was from 10 days to 36 months. Lesions were superficial punctate keratopathy in 10 cases with cornea and obstruction of inferior punctum in 2, stenosis of nasolacrimal duct in 1 and suspected occlusion of the nasolacrimal duct in 1 with lacrimal duct. Local therapy was eye drops in all cases. Of the whole 12 patients, S-1 was continued or discontinued in 6 each of all 12 cases, in 5 each of 10 cases with superficial punctate keratopathy, and in 2 each of 4 cases with lacrimal duct lesions. Epiphora/optic lesions improved with a range from 10 days to 1.5 months in cases of discontinuation and with that from 2 weeks to 1 month in cases of continuation.. Our results revealed superficial punctate keratopathy in many cases, lacrimal duct lesions in a few cases, and discontinuation of medication provided improvement of optic events.. When epiphora is observed in patients on S-1 therapy, it is necessary to assess optic disorders by an opthalmologist immediately because of suspicion of injury to the cornea and lacrimal duct.

Topics: Adult; Aged; Aged, 80 and over; Drug Combinations; Eye Diseases; Female; Humans; Lacrimal Apparatus Diseases; Male; Middle Aged; Neoplasms; Oxonic Acid; 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

Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999-2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. 'S-1 and low-dose cisplatin therapy' without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, 'alternate-day S-1 regimen' may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. < or =Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1.

Topics: Animals; Antimetabolites, Antineoplastic; Drug Combinations; Fluorouracil; History, 20th Century; History, 21st Century; Humans; Neoplasms; Oxonic Acid; Tegafur

79 patients(almost gastric cancer), who took drug S-1for the period from November 2000 to February 2006 in Asahi Rosai Hospital, were placed in two groups--a continuous group and a withdrawal group--to investigate and discuss the background factors contributing to the alleviation of digestive medication toxicity. The average number of days elapsed until drug withdrawal was 20 days, approximately 60% of the causes for withdrawal being attributable to digestive symptoms. A comparison between a subgroup of post-gastrectomy patients and a subgroup of non-gastrectomy patients showed that single S-1 drug administration could be continued for a longer period in the former than in the latter (p<0.05). A comparative study on drug regimens among all the patients demonstrated that a two-week regimen allowed the drug to be continuously administered for a longer period than a three- or four-week regimen(p<0.05). It was suggested that adverse effects might be alleviated by suppressing acid secretion in the stomach in the post-gastrectomy group. For the patients in that group, drug withdrawal is almost impossible. Considering that the average number of days elapsed until drug withdrawal is approximately 20 days, there seems to be a pressing need to establish the two-week regimen for continuous S-1 administration, which is not contained in the attachment hereto.

Topics: Antineoplastic Combined Chemotherapy Protocols; Digestive System Diseases; Drug Combinations; Humans; Medical Records; Neoplasms; Oxonic Acid; Patient Care; Retrospective Studies; Tegafur

We report a 63-year-old man with recurrent gastroesophageal junction adenocarcinoma. He underwent esophagogastrectomy in August 2004. After curative operation with Stage III (pT3N1M0), a recurrence was found at the anastomosis site in November 2004. Chemoradiotherapy with S-1 followed by chemotherapy (S-1) was performed from January 2005 to April 2006. Lymphnode metastasis to the left side of the main bronchus appeared in May 2006, and paclitaxel was used until December 2007 when PR was indicated by CT scan and GIF. Now he is receiving CPT-11. During these 3 years and 3 months, his performance status was maintained from 0 to 1.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Combined Modality Therapy; Drug Combinations; Esophageal Neoplasms; Humans; Irinotecan; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Oxonic Acid; Paclitaxel; Quality of Life; Stomach Neoplasms; Tegafur; Time Factors; Tomography, X-Ray Computed

Although it is recommended that the standard S-1 dosage should be based on how large the body surface area is, an on-site setting of the appropriate dosage is often lower than the standard one, depending on the individual's condition and considering possible side effects and so, on. Here, we investigated usage conditions for S-1 as a part of field training for expert pharmacists at our hospital that performs total clinical treatments. Decreases in dosage per day for elderly patients were although the standard dosage is generally determined according to the amount of a patient's body surface. We conducted a retrospective survey with a total 90 patients by creating a tree-diagram to identify a reduction standard. It was found that the S-1 dosage was decreased when there were side effects, aggravation in performance status, decrease in kidney function, old age, combined injection chemotherapy, and a decrease in radiation therapy performance. The dosage decreases without such medical reasons were seen in only 4 of the 90 patients. The individual target dosage on the basis of daily medical examination.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Combinations; Female; Hospitals; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Tegafur

TS-1 (S-1), developed by the scientific theory of both potentiating antitumor activity of 5-fluorouracil (5-FU) and reducing gastrointestinal toxicity induced by 5-FU, is a new oral formulation consisting of 1 M tegafur, 0.4 M gimeracil and 1 M oteracil potassium. We investigated the antitumor efficacy of S-1 alone and in combination with other cytotoxic anticancer drugs using subcutaneously or orthotopically implanted murine and human tumors in rodents. As a single agent, S-1 showed higher antitumor activity with its low intestinal toxicity compared to continuous venous infusion 5-FU, the most effective dosing method of 5-FU, and/or to clinically available oral fluoropyrimidines such as UFT, doxyfluridine and capecitabine on various murine tumors and human tumor xenografts. Especially, it was noteworthy that S-1 as a DPD-inhibitory fluoropyrimidine markedly affected human tumor xenografts with high expression levels of DPD on which other fluoropyrimidines showed a low antitumor activity. In combination with other anticancer drugs such as CPT-11 and taxanes, S-1 exercised synergistic antitumor efficacy not only on 5-FU-sensitive tumors with low expression levels of thymidylate synthase (TS) but also on 5-FU-resistant tumors with originally higher and/or elevated levels of TS expression. As one of the reasonable mechanism of antitumor synergism by the combination, CPT-11 and taxanes were found to reduce the expression of TS in human tumor resistant to 5-FU with high expression TS levels. Throughout our preclinical antitumor studies of S-1, alone and/or in combination with other anticancer drugs, it would be expected to contribute greatly to the treatment of cancer patients.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Mice; Neoplasm Transplantation; Neoplasms; Oxonic Acid; Pharmaceutical Preparations; Rats; Sarcoma, Yoshida; Tegafur; Uracil

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Fluorouracil; Humans; Neoplasms; Oxonic Acid; Pyridines; Tegafur; Uracil