s-1-(combination) and Disease-Models--Animal

5-Fluorouracil (5-FU), a core anticancer agent for malignancies, induces gastrointestinal (GI) toxicities. Despite recent advances in tumor immunology, it still remains unknown how GI toxicities affect antitumor immunity. S-1 is a tegafur-based oral 5-FU prodrug which has been widely introduced in Japan and other countries. The alternate-day S-1 administration has been proposed to minimize its GI and other toxicities without reducing its anticancer efficacy.. In this study, two S-1 administration regimens were compared in mice to evaluate their impact of GI toxicities on immunity. In the daily group as a standard administration model, S-1 was administered for 14 days on and 14 days off, and in the alternate-day group as a non-GI toxicity model, S-1 was administered every other day for 28 days. As well as physical findings, regulatory T cells, Th1 cells and other cells in murine lymphoid tissues were analyzed with flow cytometry.. Only the daily group exhibited body weight loss and GI toxicities. In the daily group, a proportion of regulatory T cells in the intestinal lymphoid tissue were demonstrated to be six-fold higher than in the control without S-1, and the proportion of Th1 cells showed a decreasing trend. However, the alternate-day group exhibited almost no change in T-cell subsets.. GI toxicities of 5-FU may have a negative influence on antitumor immunity due to increased proportions of regulatory T cells and decreased proportions of Th1 cells. The alternate-day S-1 administration may be a useful regimen with its minimal influence on T-cell subsets.

Topics: Animals; Antimetabolites, Antineoplastic; Disease Models, Animal; Drug Combinations; Fluorouracil; Gastrointestinal Diseases; Gastrointestinal Tract; Male; Mice; Mice, Inbred BALB C; Oxonic Acid; T-Lymphocytes, Regulatory; Tegafur

Thymidylate synthase (TS), a target enzyme of 5-fluorouracil (5-FU), is significantly associated with prognosis in various cancers. Recently, it has been reported that S-1, a novel 5-FU-based agent has an effect on bladder cancer. However, in cells with high TS level, S-1 did not have significant effects. Therefore, we examined whether down-regulation of TS enhanced effects of S-1 in them. First, we measured TS level in an aggressive bladder cancer cell line, KU-19-19 by enzyme-linked immunosorbent assay (ELISA) and evaluated its sensitivity to 5-FU using a small interfering RNA (siRNA) for TS. Next, we measured TS mRNA after exposure to various agents. Finally, we evaluated enhancement of cytotoxicity of S-1 by CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) which down-regulated TS in in vivo study. The median TS and dihydropyrimidine dehydrogenase (DPD) level was 53.3 ng/mg and 80.3 ng/mg in KU-19-19 cells, respectively. The 5-FU treatment in KU-19-19 cells transfected with siRNA for TS gene (TYMS) inhibited cell growth more significantly than that for nontargeting control. Down-regulation of TS was observed after exposure to SN-38 (7-ethyl-10-hydroxycamptothecin) in a dose-dependent manner. The combination treatment of 5-FU and SN-38 significantly inhibited cell growth, as compared to the single treatment. Meanwhile, in cells transfected with siRNA for TYMS, neither an additive nor a synergistic effect was observed. Also, combined S-1 and CPT-11 dramatically inhibited tumor growth, compared to S-1 or CPT-11 alone in in vivo study. In conclusion, CPT-11 down-regulated TS level and enhanced the effect of S-1. Thus, the combination therapy with S-1 and CPT-11 might be a novel modality for bladder cancer, even with high TS level.

Topics: Animals; Camptothecin; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Mice; Mice, Nude; Oxonic Acid; RNA Interference; RNA, Small Interfering; Tegafur; Thymidylate Synthase; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Human malignant pleural mesothelioma (HMPM) is an aggressive neoplasm that is highly resistant to conventional therapies. We established 3 HMPM cell lines (TCC-MESO-1, TCC-MESO-2 and TCC-MESO-3) from Japanese patients; the first 2 from the primary and metastatic tumors of a patient with the epithelioid type of HMPM, and the third from a patient with biphasic characteristics of the tumor (epithelioid and sarcomatous phenotypes). The 3 cell lines resembled the original HMPMs in their morphological and biological features, including the genetic alterations such as lack of p16 expression and mutation of p53. Their tumorigenicity was determined in SCID mice by orthotopic implantation (20-46%). The tumorigenicity of the HMPM cell lines, which was relatively low, was enhanced by repeated subcultures and orthotopic implantations, and 3 competent tumorigenic sublines were produced (Me1Tu, Me2Tu and Me3Tu sublines from the TCC-MESO-1, TCC-MESO-2 and TCC-MESO-3 cell lines, respectively). The resultant HMPM sublines efficiently generated tumors in the SCID mice (100%) following orthotopic implantation. SCID mice implanted with the competent sublines, into one of which the luciferase gene was introduced, displayed quantitative fluctuation of the bioluminescence for the tumor volume in vivo. Oral administration of S-1, an anticancer agent, suppressed the proliferation of the luciferase gene-expressing Me1Tu subline in the mouse models in vivo, with a treated-to-control ratio of the mean tumor volume of 0.2. The orthotopic implantation mouse model proved to be useful for quantitative evaluation of the efficacy of novel anticancer drugs and also for studying the biology of HMPMs in vivo.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Cell Line, Transformed; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p16; Cytokines; Disease Models, Animal; Drug Combinations; Humans; Immunoenzyme Techniques; Luciferases; Male; Mesothelioma; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Middle Aged; Neoplasm Proteins; Oxonic Acid; Photons; Pleural Neoplasms; Tegafur; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Metronomic chemotherapy has been advocated recently as a novel chemotherapeutic regimen. Polyethylene glycol (PEG)-coated liposomes are well known to accumulate in solid tumors by virtue of the highly permeable angiogenic blood vessels characteristic for growing tumor tissue, the so-called "enhanced permeability and retention (EPR) effect". To expand the range of applications and investigate the clinical value of the combination strategy, the therapeutic benefit of metronomic S-1 dosing in combination with oxaliplatin (l-OHP)-containing PEG-coated liposomes was evaluated in a murine colon carcinoma-bearing mice model. S-1 is an oral fluoropyrimidine formulation and metronomic S-1 dosing is a promising alternative to infused 5-FU in colorectal cancer therapy. Therefore, the combination of S-1 with l-OHP may be an alternative to FOLFOX (infusional 5-FU/leucovorin (LV) in combination with l-OHP), which is a first-line therapeutic regimen of a colorectal carcinoma. The combination of oral metronomic S-1 dosing with intravenous administration of liposomal l-OHP formulation exerted excellent antitumor activity without severe overlapping side-effects, compared with either metronomic S-1 dosing, free l-OHP or liposomal l-OHP formulation alone or metronomic S-1 dosing plus free l-OHP. We confirmed that the synergistic antitumor effect is due to prolonged retention of l-OHP in the tumor on account of the PEG-coated liposomes, presumably via alteration of the tumor microenvironment caused by the metronomic S-1 treatment. The combination regimen proposed here may be a breakthrough in treatment of intractable solid tumors and an alternative to FOLFOX in advanced colorectal cancer therapy with acceptable tolerance and preservation of quality of life (QOL).

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Humans; Liposomes; Male; Mice; Mice, Inbred BALB C; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Polyethylene Glycols; Tegafur; Treatment Outcome; Tumor Burden

To investigate the usefulness of S-1 for the treatment of peritoneal metastasis from colon cancer using a colon cancer peritoneal metastasis model.. Colon 26 PMF-15 cells were transplanted intraperitoneally into mice. The concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) in the plasma and peritoneal tissue of the mice were determined at 6 sampling time points, i. e., pre-dosing and at 30min, 1, 2, 4 and 8 hrs after oral administration of S-1 (10mg/kg equivalent of FT) on day 20 post-transplantation.. The AUC0-8h values of both 5-FU and CDHP were greater in the peritoneal tumor tissue than in the normal peritoneal tissue. The AUC of 5-FU in the peritoneal tumor tissue was 2. 90 times higher than that in plasma.. The results suggest that S-1 may exert an antitumor effect on peritoneal metastasis arising from colon cancer and be potentially useful as a therapeutic agent in cases of colon cancer with peritoneal metastasis, which is generally recognized as carrying an unfavorable prognosis.

Topics: Administration, Oral; Animals; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Drug Combinations; Male; Mice; Neoplasm Transplantation; Oxonic Acid; Peritoneal Neoplasms; Tegafur

We evaluated the therapeutic effect of TS-1, a novel oral fluoropyrimidine, in combination with leucovorin with in vivo experiments using a murine tumor xenograft model fed a low folate diet. The reduced folate levels in the tumors of mice fed a low folate diet were significantly lower than those in the tumors of mice fed a normal diet. In addition, the basal reduced folate levels in the tumors of mice fed a low folate diet were comparable to those in human colorectal cancer tissues. Furthermore, when leucovorin was orally administered, the reduced folate levels in the tumors of mice fed a low folate diet were more than two-fold higher than those of mice fed the normal diet. The leucovorin-induced potentiation of TS-1 antitumor activity was obviously higher in COL-1 tumor-bearing mice fed a low folate diet than in mice fed a normal diet. The remarkable increase in reduced folate levels following the administration of leucovorin contributed to the leucovorin-induced potentiation of TS-1 antitumor activity in this low-folate-diet animal model. These results suggest that rodent models fed a low folate diet are suitable for in vivo evaluation of reduced folate drugs like leucovorin. In this model, the combination of leucovorin with TS-1 resulted in a higher antitumor efficacy than TS-1 alone or the combination of UFT and leucovorin, suggesting that TS-1 and leucovorin combination therapy may be an effective regimen for patients with colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diet; Disease Models, Animal; Drug Combinations; Drug Evaluation; Folic Acid; Humans; Leucovorin; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Oxonic Acid; Tegafur

To evaluate the antitumor and antimetastatic efficacy of oral fluoropyrimidines, alone and combined with taxane on human breast cancer xenografts model, we developed a breast cancer model that spontaneously metastasizes to the lung by orthotopic implantation of MDA-MB-435S-HM tumors into the mammary fat pad (mfp) of SCID mice. The activity of the 5-fluorouracil (5-FU)-degrading enzyme dihydropyrimidine dehydrogenase (DPD) was significantly higher in the metastatic tumors than in the primary tumors. Based on this enzymatic characteristic of pulmonary metastases of breast cancer in regard to 5-FU metabolism, we investigated the antitumor activity of two types of oral 5-FU prodrugs, with and without paclitaxel, on both orthotopically implanted breast tumors and metastatic lung tumors in mice. The drugs and doses used were: S-1, a new oral DPD-inhibiting fluoropyrimidine (DIF) 8.3 mg/kg/day, capecitabine 360 mg/kg/day as a non-DIF, and paclitaxel 50 mg/kg, all of which display minimal toxicity in mice. In the primary tumors, paclitaxel and S-1 displayed a significant antitumor activity, with 57 and 41%, respectively inhibition of tumor growth (p < 0.01), but capecitabine had no effect. When S-1 and paclitaxel were combined, they synergistically caused tumor regression (tumor growth inhibition ratio 94%, p < 0.01) in mice compared to capecitabine plus paclitaxel, without any toxicity. In the pulmonary metastasis model, paclitaxel, and both S-1 alone and combined with paclitaxel, but not capecitabine alone or combined with paclitaxel, diaplayed almost complete antimetastatic activity. These results strongly suggest that combination of S-1, as a DIF with taxanes will show a potent high antitumor and antimetastatic effect on refractory human breast cancers, especially those expressing strong DPD activity.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Disease Models, Animal; Drug Combinations; Female; Mice; Mice, SCID; Neoplasm Metastasis; Oxonic Acid; Paclitaxel; Pyridines; Tegafur; Transplantation, Heterologous

Recent clinical trials have suggested that oral administration of a new anti-cancer agent, S-1, seems a promising therapy for advanced gastric cancer. In this study, we assessed the efficacy of S-1 against peritoneal dissemination of gastric cancer in a newly developed animal model and investigated the efficacy of S-1 from a pharmacokinetic angle.. Human gastric cancer cells (MKN-45) were injected into the peritoneal cavity of nude mice. The cancer cells were transduced using an enhanced green fluorescent protein (EGFP)-expressing plasmid vector, enabling micrometastatic foci to be accurately assessed with a high level of detection sensitivity. To investigate pharmacokinetics, the concentration of 5-FU was determined in tumor, peritoneum and plasma.. Fourteen and 21 days after intraperitoneal injection, a significant difference in the number of fluorescent foci was observed between the control group and the S-1 group (p = 0.02 and p = 0.0024, respectively. The therapeutic effect of S-1 was significantly greater than that of 5-FU. Furthermore, S-1 treatment greatly improved the survival time and cachexia. The area under the curve of 5-FU in tumor was higher than in the peritoneum and plasma.. Oral S-1 is a promising chemotherapy for peritoneal dissemination of gastric cancer.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Disease Models, Animal; Drug Combinations; Female; Fluorouracil; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Fluorescence; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Stomach Neoplasms; Tegafur; Tumor Cells, Cultured

Favorable results have been reported for the novel oral anticancer agent S-1 (TS-1) in clinical studies of advanced gastric cancer with peritoneal dissemination. In the present study we assessed its pharmacokinetics, inhibitory effects, and effect on survival time in an animal model.. A model of peritoneal dissemination was created by intraperitoneally implanting 4-week-old female BALBc nu/nu mice with the human gastric cancer cell line MKN-45 after transfection with a fluorescent protein-expressing vector. Pharmacokinetics were investigated by measuring intratumor, peritoneal lining, and blood concentrations after the administration of S-1 and fluorouracil (5-FU). The effect of S-1 on survival time was also assessed, by administration once daily to seven animals per group, starting on day 7 after implantation, and survival time was compared with that of an untreated control group. The inhibitory effect of S-1 on peritoneal dissemination was evaluated by killing mice at the start of administration, and 1 and 3 weeks after the start of administration, and examining them for the presence of peritoneal dissemination under a fluorescence stereomicroscope.. Maintenance of high 5-FU concentrations in the intraperitoneal tumors was confirmed in the S-1 group, and survival time was prolonged without any decrease in oral food intake or body weight.. Assessment in a model of peritoneal dissemination of gastric cancer showed that the novel oral anticancer agent S-1 was effective against peritoneal dissemination, and that it improved the survival rate.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Disease Models, Animal; Drug Combinations; Eating; Female; Fluorouracil; Japan; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Stomach Neoplasms; Survival Analysis; Tegafur; Time Factors

S-1 is a novel oral fluorouracil antitumor drug that combines tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD), and potassium oxonate (Oxo). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the DPD inhibitory effect and lead to increased 5-fluorouracil (5-FU) concentrations. We sought to determine the influence of impaired renal function on the pharmacokinetics of S-1 in an animal model and in patients with gastric cancer.. An experimental renal failure model induced by cisplatin was developed in rabbits, and plasma concentrations of FT, 5-FU, CDHP and Oxo were determined after S-1 injection. Four patients with various degrees of renal impairment with unresectable gastric cancer were recruited to the study, and the pharmacokinetics in these four patients were analyzed following single and consecutive S-1 administrations.. In experimental renal failure, plasma clearance of CDHP and 5-FU was retarded corresponding to the degree of renal impairment and there was a close correlation between creatinine clearance (CLcr) and plasma CDHP and 5-FU clearance. In the single administration study, half standard dose was used in three patients (CLcr > or = 50 ml/min) and one-third in the other (CLcr <50 ml/min). In patients with CLcr more than 75 ml/min, C(max), T(max), AUC((0-infinity)), and T(1/2) of 5-FU and CDHP were not different between single and consecutive administrations. In contrast, in patients with mild and moderate renal dysfunction (CLcr 55 and 36 ml/min, respectively), the T(1/2) values of CDHP with consecutive administrations (7.6 and 15.3 h, respectively) were longer than the values with single administration (4.6 and 8.2 h, respectively). The T(1/2) of 5-FU was 5.7 h with single administration and 8.5 h with consecutive administration in patients with moderate renal impairment. The AUC((0-infinity)) of 5-FU with consecutive administrations (3089.7 ng.h/ml) was far greater than with single administration (430.4 ng.h/ml). There was also a strong correlation between CLcr and plasma CDHP clearance. Based on the pharmacokinetics following multiple consecutive administrations, S-1 administration resulted in no severe adverse reactions in any of the four patients.. CDHP clearance was prolonged in the presence of renal impairment, leading to a delayed T(1/2), and high AUC of 5-FU. These findings demonstrate that administration of S-1 to patients with impaired renal function may need individualized dosing and pharmacokinetic monitoring.

Topics: Aged; Animals; Antimetabolites, Antineoplastic; Cisplatin; Disease Models, Animal; Drug Combinations; Humans; Kidney Function Tests; Male; Middle Aged; Oxonic Acid; Pyridines; Rabbits; Renal Insufficiency; Stomach Neoplasms; Tegafur

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Disease Models, Animal; Drug Combinations; Drug Evaluation; Mice; Mice, Nude; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Stomach Neoplasms; Tegafur

An experimental model of tumor dormancy therapy for advanced head and neck carcinoma was developed. After transplantation of KB cells into nude mice, the mice were given tiracoxib, a selective cyclooxygenase (COX)-2 inhibitor, probucol, an antioxidant, and S-1, an oral pro-drug of 5-fluorouracil (5-FU), or combinations of two of them. The combined administration of tiracoxib with probucol significantly inhibited the tumor growth. The angiogenesis in this group was markedly reduced. Tiracoxib and probucol did not affect the intratumoral concentration of 5-FU when coadministered with S-1. The combined use of tiracoxib and probucol is thus a candidate for use in maintenance therapy after the primary therapy for patients with advanced head and neck carcinoma.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Biotransformation; Cell Division; Cell Survival; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Combinations; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Isoenzymes; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Organic Chemicals; Oxonic Acid; Probucol; Prodrugs; Prostaglandin-Endoperoxide Synthases; Pyridines; Tegafur; Telomerase; Xenograft Model Antitumor Assays

In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra) against colorectal cancer, S-1, a combination agent including a prodrug of FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, and potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribosylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinically relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fold higher than that of either FT or FUra. S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FUra and FT, were not observed with S-1. In an attempt to understand the basis for the observed superior therapeutic selectivity with S-1, we studied pharmacokinetic analysis of FUra, drug-induced apoptosis, suppression of mitosis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT administration. The peak plasma FUra concentrations derived from FUra or S-1 (FT) at comparable MTDs were similar, but the plasma level of FUra was higher with S-1 than with FUra. Induction of high and sustained apoptosis was achieved with S-1. Although the initial level of apoptosis induced by FUra was comparable to S-1, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition. Mitotic figures were more greatly suppressed with S-1 treatment than with FUra. Studies on TS inhibition indicated that, although both S-1 and FUra caused a 4- to 6-fold induction of total TS protein, single oral administration of S-1 was superior to 24-h infusion of FUra in suppressing free TS. The data are consistent with the observation that the therapeutic efficacy of S-1 (100% cure) over FUra is associated with high and sustained levels of drug-induced apoptosis, greater suppression of mitosis, and inhibition of free TS in tumor tissues.

Topics: Animals; Antineoplastic Agents; Apoptosis; Colorectal Neoplasms; Disease Models, Animal; Drug Combinations; Female; Fluorouracil; Mitosis; Neoplasm Transplantation; Oxonic Acid; Prodrugs; Pyridines; Rats; Rats, Inbred F344; Tegafur; Thymidylate Synthase; Treatment Outcome