S-1 review from preclinical pharmacology

S-1, developed by the scientific theory of both potentiating the antitumor efficacy of 5-fluorouracil (5-FU) and reducing the gastrointestinal (GI) toxicity induced by 5-FU, is a new oral formulation consisting of 1 M tegafur, 0.4 M gimeracil, and 1 M potassium oteracil. By combining gimeracil, a potent inhibitor of 5-FU degradation, and potassium oteracil, which protects against 5-FU-induced GI toxicity to tegafur, S-1, as a dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine (DIF), showed higher antitumor activity, with low intestinal toxicity, compared to continuous infusion of 5-FU (the most effective dosing schedule for 5-FU) and compared to clinically useful oral fluoropyrimidines in various murine and human tumors. In regard to combinations of S-1 with other anticancer drugs, S-1 plus CDDP markedly prolonged survival time in mice suffering gastrointestinal (GI) tumors compared to S-1 in combination with mitomycin-C and/or adriamycin. Furthermore, in combination with irinotecan and taxanes (docetaxel), S-1 exercised synergistic antitumor efficacy not only against 5-FU-sensitive GI cancers with low expression levels of thymidylate synthase (TS) but also against 5-FU-resistant GI tumors with originally elevated levels of TS expression. As one of the reasonable mechanisms of anticancer synergism exerted by an S-1 combination, irinotecan and docetaxel were found to downregulate the expression of TS in gastric cancers. Throughout our pharmacological studies of S-1, alone and in combination with other anticancer drugs, we found that S-1 could be expected to contribute greatly to the treatment of patients with gastric cancer.     

Antitumor activity and function of S-1, a new oral tegafur-based formulation

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.     

Combined therapy with a thymidylate synthase-inhibiting vector and S-1 has effective antitumor activity against 5-FU-resistant tumors

High levels of intratumoral thymidylate synthase (TS) expression are associated with resistance to 5-fluorourcil (5-FU). In order to establish a new treatment method for 5-FU-resistant tumors, the efficacy of gene therapy was investigated using an adenoviral vector expressing short hairpin RNA (shRNA) targeting TS. A replication-deficient recombinant adenoviral vector expressing shRNA targeting TS was constructed under the control of the human U6 promoter (Ad-shTS). Three 5-FU-resistant cancer cell lines, DLD-1/5FU, KM12C/5FU and NUGC-3/5FU, were used. Transduction with Ad-shTS effectively downregulated TS expression in all three 5-FU-resistant tumor cells. MTT assays demonstrated that treatment with Ad-shTS significantly inhibited the growth of all three 5-FU-resistant tumor cells. Furthermore, combined treatment with Ad-shTS and 5-FU demonstrated significantly greater inhibition of tumor cell growth in comparison to 5-FU treatment alone and Ad-shTS treatment alone. S-1, a combination of tegafur, gimeracil and oteracil potassium, was used for the 5-FU treatment by in vivo experiments. The combined treatment of Ad-shTS and S-1 was found to have the strongest antitumor effect against 5-FU-resistant DLD-1/5FU xenografts in nude mice in comparison to S-1 treatment alone and Ad-shTS treatment alone. Furthermore, the apoptotic index in tumors treated with combined Ad-shTS and S-1 was significantly higher in comparison to that in tumors treated with S-1 alone and that in tumors treated with Ad-shTS alone. Consequently, the combined treatment of the TS-inhibiting adenoviral vector and S-1 has effective antitumor activity against 5-FU-resistant tumors.     

Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs

The development of a diagnostic method for predicting the therapeutic efficacy or toxicity of anticancer drugs is a critical issue. We carried out a gene expression analysis to identify genes whose expression profiles were correlated with the sensitivity of 30 human tumor xenografts to 5-fluorouracil (5-FU)-based drugs (tegafur + uracil [UFT], tegafur + gimeracil + oteracil [S-1], 5'-deoxy-5-fluorouridine [5'-DFUR], and N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine [capecitabine]), as well as three other drugs (cisplatin [CDDP], irinotecan hydrochloride [CPT-11], and paclitaxel) that have different modes of action. In the present study, we focused especially on the fluoropyrimidines. The efficacy of all anticancer drugs was assayed using human tumor xenografts in nude mice. The mRNA expression profile of each of these xenografts was analyzed using a Human Focus array. Correlation analysis between the gene expression profiles and the chemosensitivities of seven drugs identified 39 genes whose expression levels were correlated significantly with multidrug sensitivity, and we suggest that the angiogenic pathway plays a pivotal role in resistance to fluoropyrimidines. Furthermore, many genes showing specific correlations with each drug were also identified. Among the candidate genes associated with 5-FU resistance, the dihydropyrimidine dehydrogenase mRNA expression profiles of the tumors showed a significant negative correlation with chemosensitivity to all of the 5-FU based drugs except for S-1. Therefore, the administration of S-1 might be an effective strategy for the treatment of high dihydropyrimidine dehydrogenase-expressing tumors. The results of the present study may enhance the prediction of tumor response to anticancer drugs and contribute to the development of tailor-made chemotherapy.     

肿瘤患者单次和多次口服替吉奥片的药动学研究

目的：评价肿瘤患者单次和多次口服替吉奥片的药动学特征。方法： 设单次给药组10例, 给药剂量60 mg; 连续给药组9例, 每次给药剂量60 mg, 1日2次, 连续服用7 d。采用液相色谱-串联质谱法测定血浆中替加氟及其代谢物5-氟脲嘧啶（5-FU）、 吉美嘧啶 （CDHP） 和奥替拉西 （Oxo） 的浓度。采用DAS2.0药动学软件进行药动学参数的分析和计算。结果： 单次给药替加氟Cmax为 （1407±383）ng·mL-1,AUC0-t为 （15 403±8439） ng·h·mL-1, 活性代谢物5-氟脲嘧啶Cmax为 （128±36） ng·mL-1, AUC0-t为（539±138） ng· h· mL-1, 吉美嘧啶Cmax为 （222±93） ng· mL-1, AUC0-t为 （962±390） ng· h· mL-1, 奥替拉西Cmax为 （33.2±14.6） ng· mL-1, AUC0-t为 （117±64） ng·h·mL-1。与单次给药相比, 多次给药后替加氟的Cmax和AUC增加明显 （P<0.05）, 但其增加程度与理论蓄积系数接近, 而代谢物氟脲嘧啶、 吉美嘧啶及奥替拉西的Cmax和AUC无明显增加。受试者在研究期间未出现重度以上不良反应。结论： 口服替吉奥片后, 受试者耐受良好。多次给药后, 替吉奥片主要成分的药代动力学行为没有发生明显变化。     

多西紫杉醇联合替吉奥胶囊治疗晚期食管胃交界腺癌的临床观察

目的:探讨多西紫杉醇联合替吉奥胶囊治疗晚期食管胃交界腺癌的临床疗效和不良反应。方法:2009年1月—2011年1月经病理学确诊的58例晚期食管胃交界腺癌患者接受多西紫杉醇联合替吉奥胶囊治疗:多西紫杉醇35mg/m2静脉注射d1和d8,替吉奥胶囊胶囊每天70mg/m2d1～14,每3周为1个化疗周期。每2个化疗周期评价近期疗效。每个化疗周期后评价不良反应。对所有患者进行随访,评估生存情况。结果:58例患者均可评价疗效,其中完全缓解5例(8.6%)、部分缓解21例(36.2%),疾病稳定18例(31.0%),疾病进展14例(24.1%),有效率为44.8%(26/58)。中位TTP为8.0个月,MST为10.5个月。主要不良反应包括骨髓抑制、口腔炎、手足综合征和胃肠不良反应等。Ⅲ～Ⅳ级中性粒细胞减少发生率为25.9%(15/58)。结论:多西紫杉醇联合替吉奥胶囊治疗晚期食管胃交界腺癌的近期疗效较好,不良反应可以耐受。     

Evidence produced in Japan: tegafur-based preparations for postoperative chemotherapy in breast cancer

Oral fluoropyrimidine anticancer agents (oral 5-fluorouracil [5-FU]) able to be used as chemotherapy for breast cancer include tegafur–uracil (UFT), tegafur–gimeracil–oteracil potassium (S-1), doxifluridine, and capecitabine. Since the 1980s, UFT has been most widely used for postoperative chemotherapy in breast cancer. UFT is an oral preparation that was designed to achieve and maintain high concentrations of 5-FU in plasma by combining tegafur, a prodrug of 5-FU, with uracil. UFT is characterized by mild adverse events, allowing long-term treatment. The prolonged maintenance of high plasma 5-FU concentrations has been suggested to inhibit micrometastases after surgery. Recently, large clinical trials conducted in Japan have shown that UFT-based postoperative chemotherapy is therapeutically useful in patients with node-negative (n0), high-risk breast cancer. We review the results of clinical trials of postoperative chemotherapy with UFT in Japan and discuss its roles and future prospects.     

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

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.     

Significant antitumor activity of cationic multilamellar liposomes containing human interferon-beta gene in combination with 5-fluorouracil against human renal cell carcinoma

Immunotherapy is one of the most effective treatments against metastatic renal cell carcinoma (RCC). However, the response rate is not high. Therefore, more effective therapies are necessary for patients with metastatic RCC. We previously reported on the significant antitumor activity of cationic multilamellar liposome containing human interferon-beta (huIFN-beta) gene (IAB-1) against RCC. We then examined the antitumor effect of IAB-1 in combination with anticancer drugs against RCC. The cytotoxicity of IAB-1 alone, and in combination with anticancer drugs, cisplatin, adriamycin, 5-fluorouracil, gemcitabine, paclitaxel and irinotecan hydrochloride against the human RCC cell line NC65 was examined by the colorimetric method using tetrazolium salt. For the in vivo study, we used NC65 cells inoculated into the severe combined immunodeficiency mouse. The results showed that the in vitro combination therapy with IAB-1 and 5-FU was more cytotoxic than IAB-1 alone. However, synergistic cytotoxicity was not observed when combined with IAB-1 and other anticancer drugs. NC65 tumors transfected with IAB-1 in mice were smaller than those receiving an injection of empty liposome or the recombinant huIFN-beta protein. Treatment with IAB-1 in combination with 5-FU resulted in significant anticancer activity. IAB-1 enhanced the activity of thymidine phosphorylase (TP), which converts 5-FU to the active metabolite, FdUMP. In contrast, IAB-1 decreased the activity of thymidylate synthase (TS), which is a target enzyme of 5-FU. In conclusion, these findings indicate that a combination of IAB-1 and 5-FU may have enhanced antitumor activity against human RCC, suggesting its potential clinical application. The mechanism of enhanced cytotoxicity by combination therapy with IAB-1 and 5-FU may up-regulate TP activity and down-regulate TS activity.     

Clinical evaluation of S-1, a new anticancer agent, in patients with advanced gastrointestinal cancer. S-1 Cooperative Gastrointestinal Study Group

In developing a new anticancer agent, it is most important to balance the antitumor activity and toxicity of the agent. S-1 was designed to achieve high activity and low toxicity. In it tegafur, a prodrug of 5-FU, is combined with two classes of modulators. CDHP, an inhibitor of 5-FU degradation in the liver, and Oxo, an inhibitor of 5-FU phosphoribosylation in the digestive tract. In both early and late Phase II studies, S-1 was effective against advanced or recurrent gastrointestinal cancer. Toxicities were generally mild, and there were no toxic deaths.     

Reduction of 5-fluorouracil (5-FU) gastrointestinal (GI) toxicity resulting from the protection of thymidylate synthase (TS) in GI tissue by repeated simultaneous administration of potassium oxonate (Oxo) in rats

Purpose: An important cytotoxic effect of 5-fluorouracil (5-FU) is the inactivation of thymidylate synthase (TS) (EC 2.1.1.45) activity by the formation of a ternary complex consisting of covalently bound 5-fluorodeoxyuridine 5′-monophosphate (FdUMP), TS and 5,10-methylenetetrahydrofolate (CH₂FH₄). The gastrointestinal (GI) toxicity of 5-FU is also caused by its phosphorylation in the GI tract. Potassium oxonate (Oxo) competitively inhibits pyrimidine phosphoribosyltransferase (EC 2.4.2.10), which converts 5-FU to 5-fluorouridine 5′-monophosphate (FUMP) in vitro. In this study the benefits of combining Oxo and tegafur (FT), which is a masked compound of 5-FU, in reducing the GI toxicity of 5-FU and in protecting the activity of TS in the normal GI tissues were evaluated. Methods: We administered orally a preparation of 1 M FT and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) with or without 1 M Oxo (called S-1 and FT + CDHP, respectively) or vehicle only (control) to rats for ten consecutive days and compared the toxicity, the histopathological findings and the free TS activity in the GI tissues of the treated rats. Results: During the experimental periods, the signs of toxicity, such as a decrease in body weight, diarrhea and death, were only observed in the rats treated with FT + CDHP. The histopathological findings in the ileum and colon samples from rats treated consecutively with S-1 on day 1, day 4, day 7 and day 10 were less frequent and more mild than in the samples from rats treated with FT + CDHP. Furthermore, the free TS activities in the ileum samples of rats given S-1 and FT + CDHP were significantly decreased compared with the activity in samples from the control rats throughout the experimental periods. The free TS activities in GI tissues of rats treated with S-1 were higher than the TS activities in tissues from rats treated with FT + CDHP daily from day 4 to day 10, although activities in S-1-treated rat were decreased to almost same low levels as in FT + CDHP-treated rats on day 1. Conclusions: Our results suggest that repeated simultaneous administration of Oxo and FT can effectively protect the activity of TS by decreasing FdUMP via FUMP from 5-FU in GI tissue, and may lead to a reduction in GI toxicity. Received: 13 August 1999 / Accepted: 24 February 2000     

A phase II study of S-1 in patients with metastatic breast cancer — A Japanese trial by the S-1 cooperative study group, breast cancer working group

BACKGROUND: S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur (FT), 0.4 M 5-chloro-2, 4-dihydroxypyrimidine (gimeracil), and 1 M potassium oxonate (oteracil), with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric, head and neck cancers. We investigated its clinical efficacy against metastatic breast cancer. METHODS: A non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n=111) were enrolled, and 108 patients were regarded as eligible. S-1 was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times. RESULTS: Among the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CR+PR) of 41.7% (95% confidence interval: CI, 32.3-51.5%). The incidences of toxicity (> or =grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group. CONCLUSION: S-1 was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.     

多西紫杉醇联合替吉奥胶囊治疗晚期胃癌的近期疗效

目的：探讨多西紫杉醇联合替吉奥胶囊治疗晚期胃癌近期疗效及毒副作用。方法按照随机数字表法,将38例晚期胃癌患者均分为实验组和对照组,对照组患者采用多西紫杉醇、亚叶酸钙联合氟尿嘧啶方案化疗,实验组患者采用多西紫杉醇联合替吉奥胶囊方案化疗,对比2组近期疗效、不良反应发生情况以及可评价肿瘤进展时间。结果实验组患者治疗总有效率显著高于对照组,差异具有显著性（P＜0．05）;两组患者不良反应发生率及严重程度对比,差异无统计学意义（P＞0．05）;两组患者可评价肿瘤进展时间对比,差异无统计学意义（P＞0．05）。结论多西紫杉醇联合替吉奥胶囊治疗晚期胃癌能够有效提高近期疗效,且不会明显增加不良反应,也不会对可评价肿瘤进展时间产生明显影响。     

Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.     

Synergistic effects of docetaxel and S-1 by modulating the expression of metabolic enzymes of 5-fluorouracil in human gastric cancer cell lines

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.     

Correlations between antitumor activities of fluoropyrimidines and DPD activity in lung tumor xenografts

The purposes of this study were to evaluate the antitumor activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2,4-dihydroxypyridine and 1 M potassium oxonate) on human lung tumor xenografts, as compared with other fluoro-pyrimidines, and to investigate the relationships between fluoropyrimidine antitumor activities and four distinct enzymatic activities involved in the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism. S-1, UFT (1 M tegafur-4 M uracil), 5'-deoxy-5-fluorouridine (5'-DFUR), capecitabine and 5-FU were administered for 14 consecutive days to nude mice bearing lung tumor xenografts. S-1 showed stronger tumor growth inhibition in four of the seven tumors than the other drugs. Cluster analysis, on the basis of antitumor activity, indicated that S-1/UFT and 5'-DFUR/capecitabine/5-FU could be classified into another group. We investigated tumor thymidylate synthase content, dihydropyrimidine dehydrogenase (DPD) activity, thymidine phosphorylase (TP) activity and orotate phosphoribosyl transferase activity in seven human lung tumor xenografts and performed regression analyses for the antitumor activities of fluoropyrimidines. There were inverse correlations between antitumor and DPD activities for 5'-DFUR (r=-0.79, P=0.034), capecitabine (r=-0.56, P=0.19) and 5-FU (r=-0.86, P=0.013). However, no such correlations were observed for S-1 and UFT. These findings suggest that S-1 containing a potent DPD inhibitor may have an antitumor effect on lung tumors, with high basal DPD activity, superior to those of other fluoropyrimidines.     

Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer

Background

This study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU).

Methods

A total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1?M tegafur — 0.4?M 5-chloro-2,4-dihydroxypyridine — 1?M potassium oxonate (S-1 [TS-1^®]) were also compared, using three human gastric cancer xenografts in nude mice.

Results

There was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity.

Conclusion

DPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.

     

The first case of phenytoin intoxication associated with the concomitant use of phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium

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

The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP)

The product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil.The main clinical study in this application was a randomized controlled study comparing S-1 plus cisplatin with 5-FU plus cisplatin. In this study, median overall survival times of 8.6 months and 7.9 months for S-1 plus cisplatin and 5-FU plus cisplatin, respectively, were observed (hazard ratio, 0.92; 95% confidence interval, 0.80–1.05). The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded that S-1 in combination with cisplatin (75 mg/m²) was noninferior to 5-FU plus cisplatin (100 mg/m²) in patients with advanced gastric cancer and adopted a positive opinion recommending the marketing authorization for this product for the treatment of advanced gastric cancer when given in combination with cisplatin. The recommended dose of S-1 is 25 mg/m² (expressed as tegafur content) twice a day, for 21 consecutive days followed by 7 days rest (one treatment cycle), in combination with 75 mg/m² cisplatin i.v. administered on day 1. This treatment cycle is repeated every 4 weeks.The most common side effects reported in the pivotal study were anemia, neutropenia, vomiting, diarrhea, abdominal pain, weight decrease, anorexia, and fatigue.The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The full scientific assessment report and the summary of product characteristics are available on the European Medicines Agency website (http://www.ema.europa.eu).     

A case report of gastric small cell carcinoma with long survival time by adjuvant chemotherapy--reports of chemotherapy regimens for gastric small cell carcinoma

Gastric small cell carcinomas are rather rare. The incidence of small cell carcinomas of all histological types of gastric tumors is about 0.1%. Small cell carcinoma is a very aggressive cancer with a poor prognosis,and there is no effective chemotherapy to date. We experienced a case of small cell carcinoma of the stomach with relatively long survival from combination chemotherapy. A 75-year-old man underwent total gastrectomy, and liver metastasis was recognized 5 months postoperatively. We used combination chemotherapy with tegafur/gimeracil/oteracil potassium+cisplatin and irinotecan hydrochloride+cisplatin, and he has obtained a long survival time. We should gather more chemotherapy cases and establish some effective regimens for small cell carcinoma of the stomach.