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S-1 is a recently developed dihydropyrimidine dehydrogenase inhibitor fluoropyrimidine and has demonstrated high maximum plasma 5-Fluorouracil (5-FU) levels with mild toxicity, and an oral formulation has resulted in an improvement in patient quality of life. The aims of the present study were to determine the efficacy of S-1 or S-1 combined with docetaxel (DOC) using castration resistant prostate cancer (CRPC) cells and to explore their clinical potential for treating CRPC patients. LNCaP cells, androgen dependent prostate cancer (ADPC) cells and C4-2 cells, which are a CRPC subline of LNCaP cells, were used. Specimens obtained from ADPC and CRPC patients were also evaluated. The CRPC specimens and C4-2 cells exhibited significantly lower thymidylate synthase (TS) expression, a target of 5-FU, than the ADPC specimens and LNCaP cells. In vitro, C4-2 cells exhibited higher sensitivity to 5-FU than LNCaP cells. In C4-2 xenograft model, S-1 monotherapy suppressed tumor growth and low-dose DOC enhanced the anti-tumor effect of S-1. In vitro, low-dose DOC, which did not induce G2/M arrest, increased p53 and p21 and resulted in down-regulation of TS in C4-2 cells, and down-regulation of TS is considered to be responsible for the synergistic effect of S-1 in vivo. The present findings indicate that CRPC patients with androgen ablation may be good candidates for 5-FU based chemotherapy, and these regimens have attractive therapeutic potential for clinical practice, and they may have a significant impact on therapeutic options., (Copyright © 2011 UICC.)

Purpose: Sorafenib, a multikinase and tyrosine-kinase inhibitor, has anti-tumor activity in patients with advanced renal cell carcinoma (RCC). Recently, we reported that S-1 was active and well tolerated for the treatment of cytokine-refractory metastatic RCC. Therefore, we hypothesized that S-1 might be a good candidate for combination therapy with molecular targeting agents. In this study, we examined the mechanisms underlying for the synergism between S-1 and Sorafenib for RCC treatment in vitro and in tumor-bearing murine models., Methods: Human RCC cell lines were used for the in vitro cell proliferation assay. ACHN and 786-O tumors were subcutaneously transplanted into NCr-nu/nu-mice. Mice were treated with S-1 and/or Sorafenib, and tumor growth and side effects were monitored., Results: Synergistic anti-proliferative effects of Sorafenib and S-1 were clearly demonstrated in ACHN and 786-O cell lines in vitro due to the suppression of TS and E2F-1 expression. In the NCr-nu/nu model, the synergistic anti-tumor effects of S-1 and Sorafenib were again clearly seen, indicating direct synergistic effects of each drug on tumor growth., Conclusions: Our results demonstrate the synergistic activity of S-1 and Sorafenib and provided the rationale for combination therapy with S-1 and Sorafenib for the treatment of patients with advanced RCC.

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.

Objective: We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo)., Case Summaries: The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as "probable"., Discussion: The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone., Conclusion: It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.

Determination of significant associations between gene expression and predefined endpoints might improve treatment tailoring for advanced gastric cancer. We investigated the mRNA expression of 5-fluorouracil (5-FU) pathway genes in prechemotherapeutic tumor samples of primary gastric cancer to try to predict the treatment outcome of S-1 monotherapy. 5-FU pathway genes, dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP), were analyzed using quantitative real-time PCR of RNA extracted from archived formalin-fixed paraffin-embedded tissues. We selected the median value for each gene as a cutoff to separate patients into high and low gene expression groups. High OPRT gene expression was significantly associated with tumor response (P = 0.014). In a combined analysis including OPRT, patients with high OPRT and TP showed a higher overall response rate than did the remaining patients (40 vs. 10%, respectively; P = 0.002). For survival, patients with high OPRT and low TS levels showed prolonged survival in both progression-free survival (3.4 vs. 2.4 months, P = 0.024) and overall survival (11.0 vs. 8.2 months, P = 0.007). In a multivariate analysis, the combinations of OPRT and TP for response and OPRT and TS for both progression-free survival and overall survival were independent variables. To conclude, mRNA expression levels of molecular markers in formalin-fixed paraffin-embedded specimens of primary gastric tumors can be useful for identifying patients with advanced gastric cancer who would most likely benefit from S-1 treatment.

Purpose: A 3 week treatment schedule consisting of 2 weeks of S-1 therapy and 1 week of no therapy was introduced to reduce the toxicity and increase the convenience of combination chemotherapy. Hepatic dysfunction (HD) is common in patients with biliary tract cancer. A phase I study was conducted to assess the effects of a 3 week treatment schedule in Asian patients with or without HD., Methods: Forty-six patients were stratified into four groups, according to the HD criteria of the National Cancer Institute Organ Dysfunction Working Group. A three dose escalation schema was used., Results: In the normal hepatic function group, two dose-limiting toxicity (DLT) events occurred among 12 patients at the prespecified maximal dose of 100 mg/m²/day. This dose was thereby established as the maximal tolerable dose (MTD). No DLT events were observed at the predefined maximal dose of 80 mg/m²/day in the mild HD group. In the moderate HD group, two DLT events occurred among five patients treated with 80 mg/m²/day, and the MTD was defined as 70 mg/m²/day. Two of six subjects in the severe HD group experienced DLT events at doses of 60 mg/m²/day and none developed DLT events at 50 mg/m²/day., Conclusions: The MTDs for a 3 week schedule of S-1 treatment were defined in patients with or without hepatic dysfunction. A 3 week treatment regimen of S-1 might be a platform for combination with newer cytotoxic agents or biologics.

The purpose of this study was to clarify the efficacy and safety of docetaxel and cisplatin as second-line treatment for patients with S-1 refractory advanced gastric cancer. Between 1999 and 2006, 32 patients received docetaxel (60 mg/m²) and cisplatin (60 mg/m²) (Dp regimen) on day 1 every 3 weeks. This regimen was repeated at least three times at 3-week intervals until disease progression or unacceptable toxicity was detected. The overall response rate was 21.9%. Seven patients showed partial response, 17 showed stable disease and 8 showed disease progression. The median survival time was 12.3 months after the start of the first-line treatment. The median survival time and time to progression following the DP regimen was 7.8 months and 4.0 months, respectively. The major adverse effects were leukopenia and neutropnea. Non-hematological toxicities were generally mild to moderate and controllable. this study showed satisfactory therapeutic outcomes for patients with gastric cancer refractory to S- 1 chemotherapy.

Background: The goal of this study is to evaluate the effectiveness of S-1/Oxaliplatin vs. Doxifluridine/Oxaliplatin regimen and to identify miRNAs as potential prognostic biomarkers in gastric cancer patients. The expression of candidate miRNAs was quantified from fifty-five late stage gastric cancer FFPE specimens., Experimental Design: Gastric cancer patients with KPS>70 were recruited for the trial. The control group was treated with 400 mg/twice/day Doxifluridine plus i.v. with Oxaliplatin at 130 mg/m(2)/first day/4 week cycle. The testing group was treated with S-1 at 40 mg/twice/day/4 week cycle plus i.v. with Oxaliplatin at 130 mg/m(2)/first day/4 week cycle. Total RNAs were extracted from normal and gastric tumor specimens. The levels of miRNAs were quantified using real time qRT-PCR expression analysis., Results: The overall objective response rate (CR+PR) of patients treated with S-1/Oxaliplatin was 33.3% (CR+PR) vs. 17.6% (CR+PR) with Doxifluridine/Oxaliplatin for advanced stage gastric cancer patients. The average overall survival for patients treated with S-1/Oxaliplatin was 7.80 month vs. 7.30 month with patients treated with Doxifluridine/Oxaliplatin. The expression of miR-181b (P = 0.022) and miR-21 (P = 0.0029) was significantly overexpressed in gastric tumors compared to normal gastric tissues. Kaplan-Meier survival analysis revealed that low levels of miR-21 expression (Log rank test, hazard ratio: 0.17, CI = 0.06-0.45; P = 0.0004) and miR-181b (Log rank test, hazard ratio: 0.37, CI = 0.16-0.87; P = 0.018) are closely associated with better patient's overall survival for both S-1 and Doxifluridine based regimens., Conclusion: Patients treated with S-1/Oxaliplatin had a better response than those treated with Doxifluridine/Oxaliplatin. miR-21 and miR-181b hold great potential as prognostic biomarkers in late stage gastric cancer.

The combination therapy of CPT-11, a prodrug of SN-38, with S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non-small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with S-1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity. In vitro cytotoxic effects were examined in human NSCLC cell lines (A549, PC-9, PC-14, EBC-1 and H520). In vivo antitumor effects were evaluated in PC-14- and EBC-1-bearing mice after NK012 or CPT-11 administration on Days 0 and 7 and S-1 administration on Days 0-13. Pathological changes in the small intestine were also investigated. The in vitro growth inhibitory effects of NK012 were 56.8- to 622-fold more potent than those of CPT-11. NK012/S-1 treatment showed significantly higher antitumor activity both in PC-14-bearing (p = 0.0007) and EBC-1-bearing mice (p < 0.0001) than CPT-11/S-1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT-11/S-1-treated mice than in NK012/S-1-treated mice. NK012/S-1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants clinical evaluation.

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.

Neoadjuvant chemotherapy (NAC) by 5-fluorouracil including S-1 is administered to advanced gastric cancer patients. However, the therapeutic benefit from this pre-operative treatment remains uncertain. The present study analyzed the expression of 5-fluorouracil related enzymes, TS, DPD and OPRT in 47 gastric cancer biopsy specimens using quantitative double-fluorescence immunohistochemistry (qDFIHC), which is a newly developed system to quantify protein expression. The study first determined whether the cancer heterogeneity within the sample influences evaluation by qDFIHC system. Thereafter, the expression values of the TS, DPD, OPRT and OPRT/TS, OPRT/DPD, OPRT/(TS+DPD) ratios were retrospectively correlated with the clinical or pathological response in the patients. The expression values of TS, DPD and OPRT at a single field were significantly correlated with mean of the values evaluated at three fields. Among the 6 candidate factors analyzed, OPRT, OPRT/TS, OPRT/DPD and OPRT/(TS+DPD) showed significant correlations with the clinical response in 47 patients. Cut-off values to differentiate the clinical response were determined in the four factors. OPRT/TS showed the strongest correlation with the clinical response. qDFIHC was able to quantify the TS, DPD and OPRT expressions in cancer biopsy specimens without being affected by the heterogeneity. Effective therapy using tailored S-1 NAC according to the OPRT/TS ratio is therefore expected in advanced gastric cancer patients.

Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR.

Even though conventional pharmacotherapy has been demonstrated to display very efficient activity against a wide variety of diseases, several active agents (e.g., anti-tumor drugs and non-steroidal anti-inflammatory drugs) are generally needed to be administered at high doses to elicit the required therapeutic action, simultaneously leading to severe side effects. This fact is usually due to unfavourable pharmacokinetic profiles (poor biological half-life) and to the possibility of induction of resistance. In order to increase the therapeutic activity of ftorafur and diclofenac sodium along with an overcome of their important drawbacks, we investigated their formulation into a colloidal carrier based on the biodegradable polymer poly(epsilon-caprolactone). Two drug loading methods were studied: (i) surface adsorption in already formed nanoparticles after incubation in a drug solution; (ii) drug addition before interfacial polymer disposition leading to drug entrapment into the polymeric network. We hypothesized that such nanocarrier possessed very significant characteristics (e.g., unusually high drug loading and low burst release), suggesting their potential application for efficient drug delivery to targeted sites.

Purpose: To determine the most effective combination chemotherapy with S-1 against pancreatic cancer and to clarify the mechanism of synergy between S-1 and the partner drug., Methods: We tested a combination of S-1 with the following antitumor drugs in an in vitro MTT assay against pancreatic cancer cell line MIA PaCa-2: gemcitabine (GEM), cisplatin (CDDP), irinotecan (CPT-11), mitomycin C, adriamycin, and paclitaxel. The efficacy of S-1, GEM, and a combination of S-1 and GEM was also tested in vivo by administering S-1 (10 mg/kg) orally to nude mice five times a week for 3 weeks, and GEM (100 mg/kg) intravenously every 2-3 days for a total of six times. A treated-to-control ratio (T/C) of relative mean tumor weight values less than 50% was determined to be effective. Furthermore, we investigated the mechanism of the synergistic effect of S-1 and GEM on the cell cycle by flow cytometry, because both S-1 and GEM are known as antimetabolic drugs. To verify cell death induced by a change in the distribution of the cell cycle phases, we investigated apoptosis by sub-G1 analysis and a TUNEL assay., Results: From classical isobolography analysis of the in vitro MTT assay, the combination of S-1 plus GEM was found to be the most effective of the combinations tested. In vivo, T/C (percentage) with the combination of S-1 plus GEM was 48.2%, which was lower than that of S-1 or GEM alone, and the combination enhanced antitumor activity. Cell cycle analysis showed greater cell cycle delay with the combination treatment (S-1 plus GEM) than for each single drug treatment, and apoptotic cells were detected only in treatments including GEM., Conclusion: The combination chemotherapy of S-1 and GEM appears to be useful for pancreatic cancer. Both cycle delay by S-1 plus GEM and apoptosis induced by GEM are involved in this synergistic mechanism.

S-1, an oral fluorouracil antitumor drug, is composed of three agents: tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo). Approximately 50% of oral squamous cell carcinomas (OSCC) exhibit cervical lymph node metastasis. The extent of lymph node involvement is a major determinant in both staging and prognosis of the majority of OSCC. The purpose of this study was to examine the effect of S-1 on the metastatic potential of OSCC cells. We used orthotopic green fluorescence protein (GFP) SAS-L1, in BALB/c nu/nu mice. Mice received oral doses of either 5% hydroxypropylmethylcellulose (HPMC) for control or S-1 (20 mg/kg) and were autopsied at 2 weeks. We also performed in vitro experiments using concomitant 5-fluorouracil (5-FU) and CDHP as a drug model of S-1 to determine the effect of S-1 on OSCC invasion and metastasis. Although 100% (11 of 11) of mice not treated with S-1 showed cervical lymph node metastasis, only 54.4% (6 of 11) of S-1 treated mice demonstrated metastasis. In in vitro experiments, OSCC cells treated with 5-FU and CDHP showed a marked reduction in invasiveness and in adhesion to laminin coated plates. Western blot analysis revealed that treatment with 5-FU and CDHP suppressed expression of integrins alphav, alpha3, alpha6, beta1, beta3, beta4, beta5, and beta6. These results suggest that S-1 inhibits tumor proliferation and lymph node metastasis in OSCC cells. Moreover, expression of integrin subunits and the integrin signal transduction pathway may be closely related to metastasis suppression.

S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.

A number of genetic polymorphisms have been reported to affect responsiveness to (pharmacokinetics and pharmacodynamics of) pharmaceuticals, and this study field, pharmacogenomics, is rapidly developing. Several genetic biomarkers associated with drug safety and efficacy have been already applied to diagnostic and prescribing purposes. In this review, we would like to outline the recent progress in pharmacogenomics, focusing on anti-cancer drugs tegafur (with reference to CYP2A6 polymorphisms), irinotecan (UGT1A1), and cetuximab (somatic mutations in KRAS), and an anti-platelet drug clopidogrel (CYP2C19). This review also addresses genetic markers for drug-induced severe cutaneous adverse reactions (HLA-B) and myopathy(SLCO1B1).

Previous studies have assessed the efficacy and safety of combined treatment with irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin, CPT-11) and S-1, containing tegafur, a prodrug of 5-fluorouracil, in the treatment of colorectal and gastric cancer. The objective of this study was to describe the interaction between CPT-11 and S-1 in 4 patients with colorectal cancer. Coadministration of S-1 changed the pharmacokinetic behavior of CPT-11 and its metabolites. In particular, maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) of 7-ethyl-10-hydroxycampothecin (SN-38) was markedly decreased by coadministration of S-1. For SN-38, the median ratio of Cmax and AUC with S-1 to those without S-1 was median 0.34 (range 0.24-0.78) and 0.56 (range 0.23-0.68), respectively. A markedly difference in drug interaction among individual patients was observed. We conclude that the plasma concentration of SN-38 was decreased by oral administration of S-1 in patients with colorectal cancer. This observation might be important for clinical decisions regarding combination therapy.

A microfluidic device with 3-D hydrogel cell cultures has been developed to test the cytotoxicity of anti-cancer drugs while reproducing multi-organ interactions. In this device, a micro cell culture analog (microCCA), cells embedded in 3-D hydrogels are cultured in separate chambers representing the liver, tumor, and marrow, which are connected by channels mimicking blood flow. While the microfluidic network provides a platform for mimicking the pharmacokinetic and pharmacodynamic profiles of a drug in humans, the 3-D hydrogel provides a more physiologically realistic environment to mimic the tissue than monolayer culture. Colon cancer cells (HCT-116) and hepatoma cells (HepG2/C3A) were encapsulated in Matrigel and cultured in the tumor and the liver chamber in a microCCA, respectively. Myeloblasts (Kasumi-1) were encapsulated in alginate in the marrow chamber; a stiffer hydrogel was necessary to prevent cell migration out of the matrix. The cytotoxic effect of Tegafur, an oral prodrug of 5-fluorouracil (5-FU), on each cell line was tested using the microCCA with cell-embedded hydrogel. The comparison of experimental results using a 96-well microtiter plate and a microCCA demonstrated that the microCCA was able to reproduce the metabolism of Tegafur to 5-FU in the liver and consequent death of cells by 5-FU, while the cultures in a 96-well microtiter plate were unable to do so. The microCCA utilizing 3-D hydrogel cell cultures has potential as a platform for pharmacokinetic-based drug screening in a more physiologically realistic environment.

A combined pharmacokinetic-pharmacodynamic model was developed to simulate the response of a rat tumor to UFT, a combination of uracil with Tegafur (FT). Tegafur is oral the prodrug of 5-fluorouracil (5-FU), an anti-cancer drug for colon cancer. A physiologically based pharmacokinetic (PBPK) model was developed and fitted to experimental data from literature. Three pharmacodynamic (PD) models were developed to describe the tumor cell growth treated with 5-FU, and a dual transit compartment model gave the best fit. This result may be due to dual mechanisms of action of 5-FU, and the dual transit compartment model is able to simulate these better than the other models. The PBPK and PD models were combined, and various dosing strategies were tested. The optimal ratio of uracil to Tegafur to maximize tumor reduction and minimize systemic toxicity was found to be consistent with previous reports. The model correctly predicted the toxic effect of low dihydropyrimidine dehydrogenase (DPD) level, consistent with clinical tests. Pharmacokinetic modulating chemotherapy (PMC), which combines continuous infusion of 5-FU and periodic administration of UFT was shown to be more effective than the same dose given by continuous infusion only. This model can guide the development of dosing strategies and patient specific 5-FU therapies.

Objective: We evaluated retrospectively single-agent S-1 chemotherapy in non-small cell lung cancer patients in clinical practice., Methods: Sixteen consecutive patients treated with single-agent S-1 for NSCLC between July 2005 and June 2007 at the Department of Thoracic Surgery, Tsuchiura Kyodo General Hospital. The treatment schedule comprised oral administration of S-1 at 80-120 mg/day. One cycle of S-1 consisted of consecutive administration to 14 (10 cases)or 28(6 cases)days followed by a 14-day rest., Results: Patients profiles were: M/F: 11/5, median age 68 years old(range 51-83), PS 0/1/2/3: 2/6/5/3, adeno/squamous/large: 13/2/1, clinical stage 3A/3B/4: 3/4/9, prior chemotherapy regimens 0/1/2/3/4: 2/3/4/5/2, prior surgery/radiation: 12/5 were performed. Median number of delivered cycles was 5 cycles(range 1-13). Grade 3 hematological toxicities were anemia(6%)and thrombocytopenia(6%). Grade 3 non-hematological toxicities were nausea(6%)and vomiting(6%). Response of 13 patients could be evaluated after 2-4 cycles of S-1. Four partial responses were observed, for a response rate of 31%. The survival time was 67-852 days(average 14.0 months), 1-year survival rate was 74.0%, median time to progression was 4.6 m, and 1- year progression free survival was 25.0%., Conclusion: Single-agent S-1 chemotherapy has modest activity and is the one of the important regimens and tolerable for elderly, poor-PS, recurrent patients with NSCLC in clinical practice.

We evaluated the efficacy of chemotherapy using S-1 after gastrojejunostomy for unresectable gastric cancer with pyloric stenosis. We performed gastrojejunostomy to relieve obstruction in 40 patients from 1993 to 2007. After gastrojejunostomy, 15 patients were treated with S-1(S-1 group), 12 patients were treated with another anticancer drug(non S-1 group)and the other 13 patients received no chemotherapy. After informed consent was obtained, S-1(80 mg/m(2)day)and another anticancer drug was administered. The mean period of administered was 16(range 2-56)weeks in the S-1 group. In the non S-1 group, 5-FU was used in 1 patient, 5'-DFUR in 2, UFT in 3, FP chemotherapy in 3, CPT- 11/CDDP chemotherapy in 1, and 5-FU/PTX chemotherapy was conducted in 2 patients. The one-year survival rate was 63% and the median survival time was 394 days in the S-1 group, against 33% and 169 days, respectively, in the non S-1 group. Appetite loss of grade 3 was observed in one(7%)patient with nonhematological toxicity, but no patient suffered grade 3 hematological toxicity. We observed the course of all patients on an outpatient basis. In conclusion, S- 1 administration after gastrojejunostomy appears to be an effective treatment modality for far advanced gastric cancer patients with pyloric stenosis in view of toxicities, antitumor effects and QOL of the patients.

The super-selective intra-arterial infusion, which has high anti-tumor effect to infuse high concentration of drugs into arterial in the control of tumor, has been expected to have local control. 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 an active agent for squamous cell carcinoma of the head and neck(HNSCC). Docetaxel(DOC)is the drug Taxanes which has anti-tumor effect by mechanism different from conventional anti-tumor mechanism of action. In Yamaguchi University, DOC+CDDP+5-FU in the three-drug combination therapy shows high anti-tumor effect for advanced oral cancer. In the present study, we conducted a phase I study to examine local control of S-1 in the combination with DOC using super-selective intra-arterial infusion with oral cancer. The study performed super-selective intra-arterial infusion of DOC on the first day, and was considered as the schedule which prescribes three-week S-1 for patients every day from same day. Since blood toxicity nature grade 4 discovered the result in S-1: 65 mg/m(2)day and DOC: 50 mg/ m(2), we decided that recommended dose(RD)was S-1: 65 mg/m(2) and DOC: 40 mg/m(2).

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.

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].

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.

In addition to the direct cytotoxic effects of chemotherapy agents on tumor cells, the anti-angiogenic activities attained by these agents by targeting proliferating endothelial cells in tumor blood vessels has attracted much research interest. In this study, we examined the antitumor activity of 5-Fluorouracil (5-FU)-based drugs (S-1 [1M tegafur, 0.4M 5-chloro-2,4-dihydroxypyridine and 1M potassium oxonate] and capecitabine) on human colorectal cancer xenografts and evaluated their anti-angiogenic effects. Both drugs showed significant antitumor activities against COL-1 xenografts at a sub-maximum tolerated dose (sub-MTD), which was lower than the maximum tolerated dose (MTD). At the sub-MTD, a significant reduction in the microvessel number and the enhancement of tumor-associated microvessel endothelial cell apoptosis was seen in xenografts treated with S-1. In addition, we found that thrombospondin-1 (TSP-1) expression, known to be a mediator of the anti-angiogenic effects of metronomic chemotherapy, was significantly up-regulated in xenograft tumor tissues and plasma in animals treated with S-1 at a sub-MTD. Capecitabine also showed a trend toward the induction of TSP-1. These results suggest that 5-FU-based drugs inhibit tumor progression through different modes of action, including cytotoxic activity derived from 5-FU and the inhibition of angiogenesis through the induction of TSP-1.

Background: S-1 is the most effective oral fluoropyrimidine derivative widely used for patients with gastric carcinoma in Japan. Although S-1 plus taxane has been a promising candidate as an effective chemotherapeutic regimen, the mechanisms of its additive or synergistic anticancer effects and changes in gene expression after the administration of these agents have not yet been fully elucidated., Methods: Experimental chemotherapy was performed using human gastric carcinoma xenografts, MKN-45 and TMK-1, to examine anticancer effects and gene expressions of fluoropyrimidine metabolism-related enzymes including thymidine phosphorylase (TP), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and uridine phosphorylase (UP). Nude mice were treated with S-1, paclitaxel, and their combination. After treatment, in vivo antitumor effects of S-1, paclitaxel alone, and their combination and the effects on gene expressions of enzymes involved in 5-fluorouracil metabolism were examined using the RT-PCR method., Results: The combined use of S-1 and paclitaxel showed additive to synergistic antitumor effects on both gastric cancer xenografts. While consistent upregulation of dThPase and DPD gene expression was exhibited after administration of S-1, no further increase of dThPase gene expression after combined use of S-1 with paclitaxel was observed. There was no increase in TS gene expression after the administration of either S-1 alone or paclitaxel alone., Conclusion: These results provide some insight into the mechanism and/or rationale underlying the additive to synergistic effect of combined administration of S-1 and paclitaxel in gastric carcinoma.

Background: A pre-clinical study demonstrated that paclitaxel induced thymidine phosphorylase in the tumor tissues. The combination of paclitaxel and doxifluridine is expected to exert extra anti-tumor effects. We evaluated the efficacy of this combination in patients with unresectable or recurrent gastric cancer who had been previously treated with S-1., Methods: Registration was started to enroll 35 patients with advanced/recurrent gastric cancer, who were selected among those with measurable lesions fitting to response evaluation criteria in solid tumors, and with resistant to S-1 treatment. This regimen is consisted of paclitaxel, 80 mg/m(2), iv on days 1 and 8; and doxifluridine, 600 mg/m(2), po on days 1-14. The treatment was repeated every three weeks. Primary endpoint was response rate (RR); and secondary endpoints were overall survival (OS), progression free survival (PFS) and onset rate of adverse events., Results: From September 2003 to March 2005, 35 patients were registered: including 28 men; 7 women; median age of 66 years (range, 49-75 years); and performance status (PS) levels were, zero with 21 and one with 14 patients. In 33 eligible patients, except two, clinical usefulness was evaluated resulting in RR of 18.2% (partial response, 6; stable disease, 15; progressive disease, 10; and not evaluable, 2 patients). Median survival time was 321 days and median PFS was 119 days. Severe adverse events were found in three patients to discontinue the present treatment., Conclusions: The combination of paclitaxel and doxifluridine might be a treatment of choice as a second line chemotherapy for patient undergone S-1 treatment.

New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC50 and IC90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.

Objective: The aim of this study was to evaluate the potential role of UFT and its metabolite gamma-butyrolactone (GBL) for inhibition of angiogenesis induced by vascular endothelial growth factor (VEGF) in advanced cervical carcinoma by the determination of serum GBL and VEGF, and by immunohistochemical staining to assess VEGF protein expression, before and after UFT therapy., Methods: The subjects were 35 patients with an advanced cervical carcinoma and five healthy volunteers between 2002 and 2003 at Hiroshima University Hospital, under informed consent. The patients received two courses of oral fluoropyrimidine (UFT) therapy at a dose of 600 mg/day for 5 and 2 days off treatment. Serum GBL and VEGF was measured before and after UFT therapy by the gas chromatography mass spectrometry and ELISA-kit in 22 patients and five healthy volunteers, respectively. Immunohistochemical detection of VEGF protein was done in 35 cervical cancers. Results The mean serum GBL level before and after UFT therapy was 21.9 +/- 2.3 and 79.3 +/- 6.2 ng/ml, respectively, and it was significantly increased after UFT administration (P < 0.0001). The mean serum VEGF level before and after UFT therapy was 95.3 +/- 28.1 and 67.5 +/- 11.2 pg/ml, respectively, and it was decreased by UFT administration. In 20 out of 33 (66.6%) patients who were detected with VEGF protein, VEGF protein expression was decreased by UFT therapy. The Delta GBL value (GBL after UFT--GBL before UFT therapy) showed a significant inverse correlation with Delta VEGF value (VEGF after therapy--VEGF before therapy) (r2 = 0.940)., Conclusions: Our findings suggest that UFT and its metabolite GBL inhibit angiogenesis induced by VEGF to have an antitumor effect on cervical cancer.

Background: S-1 is an oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur, a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase (DPD); and potassium oxonate, an agent included to reduce gastrointestinal toxicity. S-1 has a potent antitumor effect on gastric cancer, even in 5-FU-refractory cases. However, there is a lack of basic information to account for this clinical outcome. This study was performed to determine the differences in antitumor effects of combined administration of 5-FU and CDHP between NUGC-3 cells and NUGC-3/5FU/L cells, which are resistant to 5-FU (established by repeated cultures of NUGC-3 with escalating concentrations of 5-FU), and to determine the mechanisms involved., Methods: Both cell lines were incubated with various concentrations of 5-FU and/or CDHP. The antitumor effect was assessed using an MTS assay and cell counts. DPD levels were assayed by using enzyme-linked immunosorbent assay. Expression of DPD and thymidylate synthase (TS) mRNA was quantified using real-time quantitative polymerase chain reaction analysis., Results: The combination of 5-FU (IC15) with CDHP exerted a synergistic antitumor effect on NUGC-3/5FU/L, but not on NUGC-3, while CDHP by itself did not affect cell growth in either cell line. Expression of DPD was not detected in NUGC-3/5FU/L. In NUGC-3/5FU/L, 5-FU-enhanced expression of TS mRNA was inhibited by the addition of CDHP. In contrast, in NUGC-3, administration of 5-FU with or without CDHP did not alter TS mRNA expression., Conclusions: The inhibitory mechanism of CDHP, which is independent of DPD, may in part contribute to the antitumor effect of S-1 even in 5-FU-resistant gastric cancer cases.

We evaluated the antitumor effect of combined therapy with tegafur/uracil (UFT) plus leucovorin (LV) (UFT/LV) and protein-bound polysaccharide, PSK, in three mouse models of transplantable tumors. UFT/LV showed antitumor effect against Meth A sarcoma, and the antitumor effect was enhanced when PSK given concomitantly. UFT/LV showed antitumor effect to Lewis lung carcinoma and PSK alone also showed antitumor effect at high dose, but a combination of UFT/LV and PSK resulted in no enhanced antitumor effect. Colon 26 carcinoma was weakly responsive to UFT/LV, and no enhancement of antitumor effect was found even PSK was used in combination. In conclusion, while the effect of PSK varies depending on tumor, combined use of UFT/LV and PSK may be expected to augment the antitumor effect.

N(3)-Hydroxyethyltegafur (3) was synthesized in 91.0% yield under a new condition. A series of novel fatty acid esters of 3 were synthesized. These fatty acid-nucleoside conjugates have shown cytotoxicities against Ec9706 cells and A549 cells, and the structure activity relationship was discussed.

It has been reported that S-1 can exert antitumor effects on various human cancers including oral squamous cell carcinoma (OSCC). However, little is known about the detailed mechanisms of the antitumor activity of S-1. In the present study, we determined whether S-1 could suppress the angiogenesis and growth of human OSCC cells in vitro and in vivo. The S-1 component (5-FU plus CDHP) significantly suppressed the growth and migration of OSCC cells and BAEC, which inhibited tubule formation in HUVECs in vitro. Also, S-1 inhibited the nuclear factor-kappaB (NF-kappaB) activity in human OSCC cells in vitro. Moreover, S-1 inhibited the expression of survival signal, phosphorylated Akt (p-Akt), and of two major proangiogenic molecules, vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), in cells implanted into the subcutaneous tissue of nude mice. The decreased expression of p-Akt, VEGF and FGF-2 correlated with decreased tumorigenicity and decreased vascularization of lesions in vivo. These findings suggest that S-1 can suppress the angiogenesis and growth of OSCC cells by inhibiting the expression of p-Akt, VEGF and FGF-2 involved in the blockade of Akt/NF-kappaB pathway.

The present study assesses the effects of neo-adjuvant chemotherapy (NAC) with uracil and tegafur (UFT) alone vs UFT plus cyclophosphamide (CPA), on the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in breast cancer tissues. Breast cancer patients were randomly assigned to 3 groups; the control (no-treatment) group (n=13), the UFT (5-8 mg/kg/day) alone group (n=10) and the UFT plus CPA (1 mg/kg/one day interval) (UC) group (n=9), and they received NAC for 2-4 weeks. A total of 32 invasive ductal breast carcinomas were used to assay for TS and DPD activity. There were no statistically significant differences in tumor size or stage classification between the 3 groups. The DPD activity was inversely and significantly correlated with the tumor size and pT, but the TS activity was not correlated with these clinicopathological factors. The TS activity was decreased by NAC with UFT, and the addition of CPA resulted in an increased inhibition of TS activity. In contrast, DPD activity was increased by NAC with UFT administration, but its increased activity was significantly inhibited by the addition of CPA. Multiple regression analyses demonstrated that the total dose of UFT was a significant variable for inhibiting TS activity, and that CPA was a significant variable for inhibiting DPD activity. The DPD activity increased by UFT can be inhibited by CPA, and this may represent one of the possible mechanisms responsible for the anti-tumor activity of 5-FU or its derivatives as enhanced by CPA.

Aim: To synthesize the selenophosphocholine analogues containing tegafur and test their antitumor activities., Methods: The cyclic glyceroselenophospholopid conjugate of tegafur was synthesized by the reaction of hexaethylphosphorous triamide with N1-(2-furanidyl)-N3-(hydroxyalkyl)-5-fluyorouracil and 1-O-hexadecyl glycerol as well as selenium in one-pot. Cyclic glyceroselenophospholopid conjugate of tegafur reacted with triethylamine to give title compounds., Results: Six new compounds have been synthesized. Their structures were confirmed by 1H NMR, 13P NMR and elemental analysis. Antitumor activity of the title compounds against PGA1 was tested., Conclusion: The reaction of triethylamine with cyclic glyceroselenophospholopid conjugate of tegafur very readily occurred, which was finished within 2 h at room temperature. The opening-ring products of trans isomers showed antimutor activity against human uriaryl bladder cancer cell more effective than that of the tegafur.

The modulation of carrageenan oligosaccharides from Kappaphycus striatum on the immune system in S180-bearing mice was investigated. The mice inoculated with S180 cell suspension were treated p.o. with carrageenan oligosaccharides (50, 100 and 200 microg/g) for 14 days. The effects of carrageenan oligosaccharides on transplantable tumors and macrophage phagocytosis, quantitative hemolysis of sheep red blood cells (QHS), lymphocyte proliferation, the activity of natural killer cells (NK), production of interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) were studied. Carrageenan oligosaccharides could significantly inhibit the growth of transplantable sarcoma S180 and increase macrophage phagocytosis, the form of antibody secreted by spleen cells, spleen lymphocyte proliferation, NK cells activity, serumal IL-2 and TNF-alpha level in S180-bearing mice. Considering all these results, it is suggested that carrageenan oligosaccharides exert their antitumor effect by promoting the immune system.

We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK-1, and MKN-1, -28, -45 and -74), in a time- and dose-dependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growth-inhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors., (Copyright 2006 Wiley-Liss, Inc.)

S-1 is an oral formulation combining tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. We examined whether Oxo reduces the immunosuppression induced by 5-fluorouracil (5-FU) in the rat. The body weight of rats treated with S-1 (FT + CDHP + Oxo) for seven consecutive days was significantly higher than that of rats treated with a combination of FT plus CDHP (FT + CDHP) for a similar period. The number of peripheral leukocytes was significantly higher in the S-1-treated rats (S-1 group) than that in the FT + CDHP-treated rats (FT + CDHP group). There was no apparent difference between the two treated groups in phenotypic changes of CD3-, CD45-, CD4-, or CD8-positive cells from the spleen or mesenteric lymph nodes. However, the natural killer activities of both spleen cells and mesenteric lymph node cells were significantly higher in the S-1 group than in the FT + CDHP group. Interleukin (IL)-2 production by spleen cells stimulated with concanavalin A was significantly lower in the FT + CDHP group than in the S-1 group. Although IL-2 production by mesenteric lymph node cells in the S-1 group was lower than that in untreated rats, it was higher than that in the FT + CDHP group. These findings suggest that Oxo in S-1 may reduce the suppression of antitumor immunity induced by 5-FU.

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 another is Oxo(potassium oxonate) which is localized in the mucosa of the gastrointestinal (GI) tract after oral administration and reduces GI toxicities provoked by 5-FU. S-1 is an oral anticancer agent in which these 3 components, FT, CDHP, and Oxo, are combined at a molar ratio of 1 : 0.4 : 1. Our conception to develop an SRC-based therapeutic drug and the preclinical concepts validated by numerous basic studies were demonstrated also in the clinical trials. In January 1999, S-1 was approved for the treatment of advanced and recurrent gastric cancers through the priority review system. From 2001 to 2005, S-1 was approved for the treatment of head and neck cancer, colon cancer, non-small cell lung cancer, and breast cancer. S-1 has been applied to acquire its expanded indications for the treatment of pancreatic cancer and biliary tract cancer. We are confident that the combined regimen of S-1 with other anticancer agents and with other therapeutic modalities will contribute to the routine medical practice of cancer treatment in the future.

The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg/m2/day for 5 days. After a washout period of 9 days, the 10 patients received two divided doses daily for 28 days. S-1 was administered orally at about 9 a.m. and 7 p.m. Plasma concentrations of 5-FU and F-beta-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition in the same 10 patients on days 1-5 of PVI of 5-FU and on days 1-5 of oral S-1. The area under the curve (AUC0-10h) of 5-FU on day 5 was 728 +/- 113 ng x hr/ml for PVI of 5-FU and 1,364 +/- 374 ng x hr/ml for S-1. The median 5-FU PVI: S-1 ratio of the AUC0-10h of 5-FU was 1.9. The AUC0-10h of FBAL on day 5 of PVI of 5-FU was 9,465 +/- 3,225 ng x hr/ml, AUC0-10h, as compared with 1,725 +/- 605 ng x hr/ml on day 5 of S-1 treatment. The AUC0-10h of uracil on day 5 was 252 +/- 60 ng x hr/ml with PVI of 5-FU and 12,582 +/- 3,060 ng x hr/ml with S-1. The AUC0-10h of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.

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.

Three strains of human esophageal carcinoma xenografts established in our institution were tested against combination chemotherapy in vivo and in vitro. TS-1 plus cisplatin (CDDP) was shown to be an effective combination against two carcinoma strains of moderately-differentiated type. Determination of the thymidylate synthase (TS) demonstrated a higher inhibition of the enzyme by adding CDDP to 5-FU, suggesting biochemical modulation. The remaining strain of poorly-differentiated type was resistant to the combination and an attempt was made to add docetaxel (DTX) to show that the three-drug combination was effective against the strain. Combination chemotherapy including TS-1 and CDDP thus appears to be useful treatment choice for esophageal carcinoma.

A 74-year-old man was revealed to have type 3 gastric cancer with synchronous multiple liver metastases. Despite treatment with TS-1 (120 mg/body), an increase in tumor size was demonstrated by computer tomography and endoscopy. We tried a course of a combination chemotherapy consisting of paclitaxel (PTX) plus doxifluridine (5'-DFUR ) to reduce the tumor. 5'-DFUR (600 mg/m(2)) was administered day 1 to 14 followed by 7 days'rest as one course. PTX (80 mg/m(2)) was infused on days 1 and 8. After 5 courses, the tumor markers decreased markedly, and computer tomography and endoscopy revealed remarkable tumor reduction which was thought to show a partial response. After 13 courses we discontinued this chemotherapy, so increase of the tumor marker was remarkable. This case suggests that PTX/5'-DFUR protocol is effective for clinical management of gastric cancer resistant to TS-1.

The patient was a 71-year-old man. Chemotherapy was conducted in two courses combining TS-1 (120 mg) and CDDP (80 mg) under the diagnosis of AFP-producing gastric cancer with multiple liver metastasis and peritoneal dissemination. Peritoneal dissemination disappeared, liver metastasis almost disappeared after completion of two courses, and the therapeutic efficacy was rated as PR. Then, the patient underwent distal gastrectomy and lymph node dissection. He received TS-1 monotherapy after surgery, but his condition gradually became worse. TS-1 and CDDP combination were given again, but an ileus resulted due to peritonitis carcinomatous. We therefore administered bi-weekly paclitaxel (80 mg/m(2)) intravenously. The ileus disappeared after one week, liver metastatic lesions and ascites were improved after completion of one course, and therapeutic efficacy was rated as PR. Grade 3 neutropenia and grade 1 alopecia occurred, but no other adverse reaction occurred. This therapy made it possible to eat foods, conduct chemotherapy safely while ambulatory. Paclitaxel can be expected to show good therapeutic efficacy and improve QOL of a peritonitis carcinomatosa patient with TS-1 resistant advanced gastric cancer.

Background: To confirm the feasibility and efficacy of biweekly irinotecan (CPT-11) plus cisplatin (CDDP) as third-line chemotherapy, the response rate (RR), overall survival and toxicity were evaluated in patients who had been treated with S-1 as a first-line and paclitaxel as a second-line chemotherapy for metastatic gastric cancer., Patients and Methods: The eligibility criteria of our study were: i) pathologically-confirmed adenocarcinoma of the stomach, ii) primary non-resectable or recurrent tumors, iii) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or less, iv) age less than 75 years, v) adequate hepatic, renal and bone marrow functions and vi) patients had received S-1 as a first-line and paclitaxel as a second-line chemotherapy and both regimens had failed. The treatment consisted of CPT-11 (60 mg/m2) and CDDP (30 mg/m2) on day 1 and day 15, repeated every 4 weeks., Results: Twenty-six patients were enrolled in this study. All the treatment was administered at the out-patient clinic except the first course for the initial 4 patients. The overall RR was 23.1% in all and 30.0% in the patients with target tumors (6 partial response, 11 stable disease, 7 progressive disease, 2 non-evaluable). Overall grade 3/4 toxicity was observed in 5 patients (19.2%) including pancytopenia, neutropenia, anemia, anorexia and elevation of AST/ALT. The time-to-treatment failure and the median survival time were 95 and 299 days, respectively., Conclusion: Biweekly CPT-11 plus CDDP was feasible for S-1- and paclitaxel-refractory metastatic gastric cancer, with moderate activity and favorable toxicity. This regimen was safely performed at the out-patient clinic as third-line chemotherapy.

To examine the effect of an oral fluoropyrimidine anti-cancer agent (S-1) on the radiosensitivity of a human oral cancer cell line with focusing on inhibition of survival signal, Akt/PKB. A human oral cell cancer cell line B88 was used. Activation of Akt/PKB in vivo was examined by immunohistochemistry, and apoptotic cells were detected by TUNEL method. Activation of Akt/PKB in vitro was investigated by Western blot and ELISA, and apoptotic cells were detected by Hoechst 33258 staining. S-1 (10 mg/kg/day or 50 microg/ml) greatly enhanced radiosensitivity in B88 cells by suppressing the activation of Akt/PKB. Significant increase in the percentage of apoptotic cells was observed in S-1 treated B88 cells. Survival signals Akt/PKB may be involved in determining radiosensitivity. S-1, an oral fluoropyrimidine anti-cancer agent can exert the enhancing effect on radiation by suppressing the activation of Akt/PKB.