TS-1 Treatment Research Articles

Evaluation of the efficacy and safety of a 3-weekly TS-1 regimen as adjuvant therapy for stage II and III advanced gastric cancer: A pilot study.

350 Background: Adjuvant therapy for stage II and III advanced gastric cancer (AGC) is essential in improving patient outcomes. The standard therapy, TS-1 at 80 mg/m2/day for 4 weeks with a 2-week rest, is recommended for 1 year or 8 courses. This study investigates the efficacy and safety of a 3-weekly adjuvant TS-1 regimen in AGC patients. Methods: We conducted an analysis of 93 patients who underwent gastrectomy with D2 lymphadenectomy and initiated a 3-weekly adjuvant TS-1 regimen between February 2017 and May 2022. The novel regimen consisted of TS-1 at 80 mg/m2/day for 2 weeks, followed by a 1-week rest, with a treatment goal of 1 year or 16 courses. Results: Among the 93 patients, 12 (13%) experienced disease recurrence during a median follow-up of 24.6 months (range: 4.2 to 63.3 months). Of the Stage II patients (n=73), 7 cases (9.5%) had recurrent disease, while 5 cases (25%) in the Stage III group (n=20) experienced recurrence. Recurrence-Free Survival (RFS) rates at 1 year, 3 years, and 5 years were 92.0% (95%CI 86.5 to 97.9), 84.7% (95%CI,76.4% to 93.9%), and 78.6% (95%CI, 65.8% to 94.0%), respectively. A total of 80 patients (86%) completed the adjuvant 3-weekly TS-1 treatment for 1 year or 16 courses, while 25 patients (26.9%) completed the treatment with dose reductions. Adverse events, primarily Grade 1 or 2 diarrhea (28%) and nausea (20%), were manageable. Conclusions: The novel 3-weekly TS-1 regimen as adjuvant therapy exhibited favorable efficacy and tolerable toxicity in AGC patients. These findings suggest the need for further investigation of this regimen in future clinical studies.

Post-synthesis Treatment of TS-1 with TPAOH: Effect of Hydrophobicity on the Liquid-Phase Oxidation of Furfural to Maleic Acid

A series of modified TS-1 catalysts was prepared by post-synthesis hydrothermal treatment of a parent TS-1 zeolite with solutions of different concentrations of tetrapropylammonium hydroxide (TPAOH). The treatment results in an advantageous improvement of the catalytic activity for the liquid oxidation of furfural with H2O2 to produce maleic acid. The highest yield of maleic acid (83%) was obtained when using 0.025 M TPAOH solution; while the maximum yield of the untreated TS-1 was 70%. The catalysts were thoroughly characterised by XRD, UV–Vis, ICP–OES, XPS, TEM, N2-adsorption, DRIFT of chemisorbed deuterated acetonitrile and TEM, in order to elucidate the origin of the catalytic improvement. The characterisation studies allowed us to conclude that, besides the well-known creation of mesopores within the zeolite primary particles, the TPAOH treatment also results in the increase of the hydrophobicity balance of the channels and cavities of the zeolites (via silanols removal). Both properties have a relevant effect on the improvement of the catalytic properties.

Highly Oriented Thin Membrane Fabrication with Hierarchically Porous Zeolite Seed

Nanosized zeolite is widely used as seed for high quality zeolite membranes fabrication, while its complicated synthesis routine limits large-scale productions. In this work, a non-nanosized cubic hierarchically porous TS-1 zeolite (HTS-1), obtained by basic hydrothermal treatment of conventional ellipsoid solid TS-1, is used as seed to prepare highly oriented thin membranes. A capillary condensation phenomenon resulting from the unique hierarchically porous structure benefits gel attachment. Moreover, abundant ledges, kinks, and terraces on the HTS-1 surface promote epitaxial growth of the membrane. In contrast, the solid TS-1 seed induces intergrowth dominantly, which results in a thick TS-1 membrane. The HTS-1 membrane demonstrates superior CO2/N2 separation properties compared to the TS-1 one. It associates with thin oriented membrane morphology, leading to exposure of a high Miller index surface and less diffuse distance and tortuosity. The results suggest beneficial effects of a hierarchically porou...

The optimal chemotherapeutic regimen in D2-resected locally advanced gastric cancer: a propensity score-matched analysis.

Adjuvant chemotherapy using TS-1 or capecitabine plus oxaliplatin improves survival outcomes after radical gastrectomy, with both regimens showing similar efficacies.A total of 494 patients with stage II‒III gastric cancer who underwent curative D2 gastrectomy and received adjuvant chemotherapy from April 2004 to June 2014 were included in this study. 219 patients received TS-1, and 275 received platinum-based chemotherapy. The disease-free survival associated with adjuvant chemotherapy with TS-1 was compared with that associated with fluoropyrimidine plus platinum chemotherapy to identify the subgroups that would benefit most from platinum-based chemotherapy. The platinum group consisted of younger individuals, more males and more stage III patients compared with the TS-1 group. To reduce selection bias and its effects on treatment results, we performed a propensity score-matched analysis.The matched cohort consisted of 219 TS-1 and 219 platinum treatment patients, respectively. In the matched cohort, the chemotherapeutic regimen did not affect disease-free survival according to stage (stage II: platinum vs. TS-1, P = 0.348; stage III: P = 0.132).According to the subgroup analysis, platinum-based chemotherapy resulted in an improved 3-year disease-free survival compared with TS-1 treatment (66.8% vs. 57.8%, P = 0.015) for patients with high-risk features (any two or more of pT4, pN3, and lymphovascular invasion positivity).Our results suggest that TS-1 alone is acceptable for patients without high-risk features, while platinum-based adjuvant chemotherapy should be administered to patients with high-risk features in D2-resected gastric cancer.

Targeting SUMO-1ylation Contrasts Synaptic Dysfunction in a Mouse Model of Alzheimer's Disease.

Synaptic dysfunction has been recognized as an early feature occurring at the onset of Alzheimer's disease (AD). Compromised neurotransmission leads over time to synaptic loss and these events correlate with the cognitive decline that progressively affects AD patients.Protein SUMOylation (Small Ubiquitin-like MOdifier) is a post-translational modification (PTM) involved in several cellular processes including synaptic transmission.We here demonstrate that cortical synaptosomes prepared from Tg2576 mice of 6months of age show an increased SUMO-1ylation, which returns back to normal levels at 20months although synaptic SUMOylation, at this age, resulted more sensible to KCl stimulus. Our previous findings have shown that increased SUMOylation at presynaptic level reduces the KCl-induced glutamate release. Accordingly, Tg2576 mice of 6 and 20months show a reduced KCl-evoked neurotransmitter (NT) release. In order to target SUMOylation, we developed two cell penetrating HIV Tat-linked peptides, namely TU-1 and TS-1. This strategy allowed us to modulate the SUMO machinery either positively (TU-1) or negatively (TS-1). As expected, Tg2576 synaptosomes treated with TU-1 exhibited a reduced NT release evoked by KCl. On the contrary, TS-1 treatment, which decreased SUMOylation, was able to normalize impaired glutamate release. Notably, an analysis of autopsy human AD brains has shown an increased SUMOylation in both cortical tissue and synaptosomal lysate. Our data indicate that SUMOylation level changes contribute to the development of synaptic alterations typically occurring at the AD onset and that SUMOylation could be a pharmacological target in AD synaptic dysfunction.

Effective hierarchization of TS-1 and its catalytic performance in cyclohexene epoxidation

The presented data showed that the chemical treatment of TS-1 with alkaline medium resulted in the formation of highly developed hierarchical structures. The esterification of the hydroxyl groups by methanol allowed modifying the hydrophobicity of TS-1 surface and obtaining truly micro/mesoporous material. The preservation of microporous characteristics was confirmed by XRD and low temperature nitrogen sorption studies. Detailed information on acidic properties of mesoporous titanosilicalites was delivered by IR studies of pyridine sorption and implicitly from 29Si MAS NMR investigations. Well-developed internal mesoporosity together with the retaining of Ti4+ atoms in tetrahedral framework positions offered 7-fold higher catalytic activity for the conversion of cyclohexene molecules than the native microporous TS-1. The selectivity to epoxide reached the value of 96% for the most efficient mesoporous titanosilicate.

Factors influencing the Fischer–Tropsch synthesis performance of iron-based catalyst: Iron oxide dispersion, distribution and reducibility

The performances of iron-based catalysts supported on SiO2, TiO2 and TS-1 for the Fischer–Tropsch synthesis (FTS) were investigated in a fixed-bed reactor. The results showed that Fe/TS-1 catalyst exhibited better FTS performance than Fe/TiO2 and Fe/SiO2 with higher CO conversion and C5+ selectivity. The desilication treatment of TS-1 further increased the FTS performance of Fe/TS-1 catalyst in terms of activity and stability. These iron-based catalysts were characterized by N2 adsorption, H2 temperature-programmed reduction, X-ray diffraction, transmission electron microscopy, scanning electronic microscopy and thermal gravimetric analysis. The factors influencing the FTS performance of the iron-based catalyst were discussed and the results indicated that not only the dispersion but also the reduction degree of iron oxides increased after desilication treatment of TS-1 support through generating more mesoporous structures and increasing the crystallinity degree of TS-1. The improved FTS activity is due to the increased dispersion of iron particles without affecting the original reducibility. The better stability is due to the enhanced heat and mass transfer as well as the high resistance against coke formation and deposition.

TS-1®服用1コース目に重篤な骨髄抑制をきたした2例

We report herein on two cases in which critical bone marrow suppression was caused in the first course of TS-1 treatment.A 79-year-old man with hypopharyngeal cancer of the right piriform fossa (cT2N0M0) underwent an operation with larynx-preserving partial pharyngectomy at our institution.Two months later, a neoplastic lesion was observed in the posterior wall from the oropharynx to the hypopharynx. It was diagnosed by biopsy as a squamous cell carcinoma, and was considered as a local recurrence. The salvage operation was planned. Oral administration of TS-1 (70 mg/m2/day) was started for the purpose of induction chemotherapy under hospitalization. However, serious bone marrow suppression happened on the 13th day. The patient developed multiple organ failure, and died two days later. On the basis of result of the autopsy, the sepsis following agranulocytosis was considered to be the cause of death.A 70-year-old-man with hypopharyngeal cancer of the right piriform sinus (cT4aN2bM0) underwent operation with a total laryngopharyngectomy. Multiple pulmonary metastasis and right cervical lymph node recurrence occurred 8 months postoperatively. Oral administration of TS-1 (74 mg/m2/day) was started. After a 2-week course of the TS-1, we had planned a break for one week.However, a feeling of general malaise developed and the patient suddenly visited the hospital on the 5th day of the wash out period. A blood test revealed remarkable bone marrow suppression, and multiple organ failure occurred with sepsis. The patient was admitted of intensive care units for multidisciplinary treatments.These two cases suggest that, even if a normally-accepted dose of TS-1 is given, severe bone marrow suppression may occur. Therefore strict and thorough observation is believed necessary in any such cases involving TS-1 treatment.

Two Cases in which Critical Bone Marrow Suppression was Caused in the First Course of TS-1 Treatment

Two Cases in which Critical Bone Marrow Suppression was Caused in the First Course of TS-1 Treatment

Evaluasi Mutu dan Penerimaan Panelis terhadap Rainbow Cake yang Dibuat dari Tepung Terigu dan Pati Sagu Lokal

Riau is one of the sago starch-producing province in Indonesia. Nowadays, sago starch has been utilized to produce various types of tradisional foods. The aim of this study was to compare the quality of rainbow cake produced by the addition of 30% sago starch and rainbow cake using 100% wheat flour and to evaluate panelist acceptance of these rainbow cakes. This study used a Completely Randomized Design (CRD) with two treatments and eight replications thus obtained 16 experimental units. The treatments were TS1 (100% wheat and 0%sago starch) and TS2 (70% wheat flour and 30%sago starch). The parameters observed were moisture, ash, sucrose and fat contents as well as panelist acceptance test. The results of this study indicated that rainbow cake of TS1 treatment (100% wheat flour and 0%sago starch) had no significant difference with rainbow cake of TS2 treatment (70% wheat flour and 30% sago starch) in case of ash and sucrose contents, but had significant effect on moisture and fat contents of rainbow cake. Based on the panelist acceptance test, the rainbow cake made from 70% wheat flour and sago starch 30% could be accepted by panelists similar to commercial rainbow cake.

Effect of TS-1 treatment by tetrapropyl ammonium hydroxide on cyclohexanone ammoximation

TS-1 has been treated with different concentrations of tetrapropyl ammonium hydroxide (TPAOH), characterized by a series of techniques, and studied in cyclohexanone ammoximation. The results show that the MFI structure of TS-1 is not destroyed, while mesopores are formed in TS-1 crystals and the pore diameters increase with the TPAOH concentrations; the amount of the framework Ti species decreases slightly at low concentrations of TPAOH, but decreases appreciably at the concentrations of TPAOH above 0.0125mol/L; the activity and the selectivity of TS-1 are not affected by the treatment, but the catalyst stability is markedly increased after the TPAOH treatment. The increase of the stability is attributed to the mesopore formation. But when the pore diameters are larger than 6.51nm, the catalyst stability begins decreasing due to the appreciable damage of the framework titanium by TPAOH.

The Effectiveness and Tolerance of TS-1 a Monotherapy for Relapsed Thymic Cancer Patient Who could not Tolerate Platinum Compounds

Background: The optimal chemotherapeutic regimens for thymic cancers still remain controversial, although systemic chemotherapy is an important therapeutic modality for unresectable thymic cancer. In general, platinumbased regimens such as CODE and ADOC are widely used. However, several serious side effects of the platinum therapy may significantly restrict its efficacy for clinical application. We herein describe a case with a good response to TS-1 treatment for relapsed thymic cancer in a patient who could not tolerate platinum compounds. Case report: A 73-year-old woman was diagnosed with thymic cancer, Masaoka stage IVa, in May 2009. She underwent the concurrent chemoradiation therapy. In September 2011, lung metastasis of the thymic cancer was noted in the right upper lobe. It was difficult to continue platinum-based chemotherapy due to various life-threatening side effects of the treatment. In June 2013, the chest CT scan revealed the growth of the right upper lobe metastatic tumor and left upper lobe atelectasis due to a metastatic polyploidy lesion in the left upper bronchus. The patient underwent partial resection of the lesion and repeat resections in June and September 2014. At the same time, the right upper lobe metastatic tumor had continued to grow. The patient received chemotherapy with TS-1 monotherapy. There were no severe toxicities and the right upper lobe metastatic tumor showed a marked reduction in size. At present, TS-1 therapy has been continued and the patient remains well with an excellent performance status. Conclusion: TS-1 may be a good alternative treatment for patients who cannot tolerate platinum compounds.

Relapsed cervicomediastinal lymph node carcinoma with an unknown primary site treated with TS-1 alone: a case report

BackgroundCervicomediastinal lymph node carcinoma with an unknown primary site is quite rare, and useful treatment of these diseases has not been established. We report here the case of a patient successfully treated with TS-1 alone after the relapse of cervicomediastinal lymph node carcinoma with an unknown primary site.Case presentationA 62-year-old man was referred to our hospital because of cervicomediastinal lymph node swelling and high serum levels of carbohydrate antigen 19-9 and carcinoembryonic antigen. Fluorodeoxyglucose-positron emission tomography/computed tomography revealed an accumulation of fluorodeoxyglucose in the left supraclavicular lymph nodes, mediastinal lymph nodes, and the pelvic cavity. Colonoscopy revealed rectal cancer, which was diagnosed by biopsy as a tubular adenocarcinoma. Because metastases from rectal cancer to the cervicomediastinal lymph nodes are rare, the patient underwent thoracoscopic mediastinal lymphadenectomy. A biopsy specimen from the paraaortic lymph nodes demonstrated papillary adenocarcinoma that was pathologically different from the rectal cancer; therefore, a diagnosis of mediastinal carcinoma with an unknown primary site was established. The patient underwent low anterior resection of the rectum for the rectal cancer, and no abdominal lymph node metastasis (pMP, N0/stage I) was found. Although radiotherapy was performed for the cervicomediastinal lymph nodes, the mediastinal carcinoma relapsed after 6 months. Because the patient desired oral chemotherapy on an outpatient basis, TS-1 was administered at a dosage of 80 mg/day for 2 weeks, followed by a 1-week rest. TS-1 treatment resulted in a decrease in the size of the cervicomediastinal lymph nodes, and the serum tumor marker levels decreased to normal after the fourth course. The patient continued TS-1 treatment without adverse events and is currently alive without recurrence or identification of the primary site at the 32nd month after TS-1 treatment.ConclusionThis is the first reported case of relapsed cervicomediastinal lymph node carcinoma with an unknown primary site treated by TS-1 alone. TS-1 treatment for the carcinoma with an unknown primary site may be useful in patients who are not candidates for systemic platinum-based chemotherapy.

Erratum to: Total gastrectomy increases the incidence of grade III and IV toxicities in patients with gastric cancer receiving adjuvant TS-1 treatment

We aimed to evaluate the safety and efficacy of TS-1 adjuvant chemotherapy in Taiwanese patients with gastric cancer.We included in this study patients with locally advanced gastric cancer who received adjuvant TS-1 or 5-fluorouracil chemotherapy after curative surgery and extended lymph node dissection between 1 June 2008 and 31 December 2012 at Chang Gung Memorial Hospital. Patient characteristics, tumor features, safety profiles and compliance with TS-1 treatment were retrospectively analyzed from medical charts.Forty patients received adjuvant chemotherapy with TS-1 and 193 with 5-fluorouracil within the study period. The 1- and 2-year overall survival rates were 90.6% and 87% in the TS-1 group and 95.4% and 86.8% in the 5-fluorouracil group (P = 0.34). The 1- and 2-year disease-free survival rates were 90.6% and 74.7% in the TS-1 group and 88% and 75.7% in the 5-fluorouracil group (P = 0.66). In the TS-1 group, tumor recurrence was more frequent in those with >15 metastatic lymph nodes than ≤15. Overall, 78.9%, 74.3%, 62.1% and 56% of patients underwent TS-1 treatment for at least 3, 6, 9 and 12 months, respectively. The most common adverse events of TS-1 were skin hyperpigmentation (55%), diarrhea (27.5%), dizziness (27.5%) and leucopenia (20%). Severe adverse events (SAEs; grade III or IV toxicity) were diarrhea (7.5%), stomatitis (7.5%), leukopenia (5%), vomiting (2.5%), anorexia (2.5%) and dizziness (2.5%). Patients who underwent total gastrectomy had a significantly greater risk of TS-1-related SAEs than patients who underwent subtotal gastrectomy (40% versus 8%, P = 0.014).The incidence of SAEs during TS-1 therapy was more common in Taiwanese patients with gastric cancer who underwent total gastrectomy compared with those who underwent subtotal gastrectomy. Clinicians must be aware of and able to manage these SAEs to maximize patient compliance with adjuvant TS-1.

Total gastrectomy increases the incidence of grade III and IV toxicities in patients with gastric cancer receiving adjuvant TS-1 treatment

BackgroundWe aimed to evaluate the safety and efficacy of TS-1 adjuvant chemotherapy in Taiwanese patients with gastric cancer.MethodsWe included in this study patients with locally advanced gastric cancer who received adjuvant TS-1 or 5-fluorouracil chemotherapy after curative surgery and extended lymph node dissection between 1 June 2008 and 31 December 2012 at Chang Gung Memorial Hospital. Patient characteristics, tumor features, safety profiles and compliance with TS-1 treatment were retrospectively analyzed from medical charts.ResultsForty patients received adjuvant chemotherapy with TS-1 and 193 with 5-fluorouracil within the study period. The 1- and 2-year overall survival rates were 90.6% and 87% in the TS-1 group and 95.4% and 86.8% in the 5-fluorouracil group (P = 0.34). The 1- and 2-year disease-free survival rates were 90.6% and 74.7% in the TS-1 group and 88% and 75.7% in the 5-fluorouracil group (P = 0.66). In the TS-1 group, tumor recurrence was more frequent in those with >15 metastatic lymph nodes than ≤15. Overall, 78.9%, 74.3%, 62.1% and 56% of patients underwent TS-1 treatment for at least 3, 6, 9 and 12 months, respectively. The most common adverse events of TS-1 were skin hyperpigmentation (55%), diarrhea (27.5%), dizziness (27.5%) and leucopenia (20%). Severe adverse events (SAEs; grade III or IV toxicity) were diarrhea (7.5%), stomatitis (7.5%), leukopenia (5%), vomiting (2.5%), anorexia (2.5%) and dizziness (2.5%). Patients who underwent total gastrectomy had a significantly greater risk of TS-1-related SAEs than patients who underwent subtotal gastrectomy (40% versus 8%, P = 0.014).ConclusionsThe incidence of SAEs during TS-1 therapy was more common in Taiwanese patients with gastric cancer who underwent total gastrectomy compared with those who underwent subtotal gastrectomy. Clinicians must be aware of and able to manage these SAEs to maximize patient compliance with adjuvant TS-1.

Role of the Ti(IV)-Superoxide Species in the Selective Oxidation of Alkanes with Hydrogen Peroxide in the Gas Phase on Titanium Silicalite-1: An In Situ EPR Investigation

The interaction of TS-1 with gaseous hydrogen peroxide at temperatures above 373 K has been investigated by in situ EPR measurements. Treatment of TS-1 with hydrogen peroxide in the gas phase leads to a strong EPR signal, assigned to the Ti(IV)-superoxide species. In contrast to investigations with liquid hydrogen peroxide, here only one Ti(IV)-superoxide species could be detected in the EPR spectrum. The time constant of the reaction of the Ti(IV)-superoxide species detected by in situ EPR measurements was much larger than that observed for the rate of consumption of propane or propene via gas chromatographic analysis. Thus, we conclude that the superoxide species may take part in the oxidation reaction (via side reactions or the formation of unselective products), but is probably not the main responsible species in the oxidation of propane or propene.

Feasibility of Bioavailability Testing by Simultaneous Determination of Serum Concentrations of Tegafur and 5-fluorouracil after TS-1 Oral or Tube Administration for Chemotherapy in Oral Cancer Patients

TS-1 is an oral anticancer agent comprising three components: two biochemical modulators of 5-fluorouracil (5-FU) and tegafur (FT), a prodrug of 5-FU. TS-1 displays potent anti-tumor activity by maintaining effective 5-FU concentrations in serum for a prolonged period. FT is gradually converted to 5-FU in vivo via 5'-hydroxylation mediated by cytochrome P450s. As a result, genetic polymorphisms can cause wide individual differences in serum concentration of 5-FU after administration of TS-1, requiring monitoring of serum concentration of 5-FU for each patient. Chemotherapy with TS-1 plays a major role in the treatment of oral cancer. In cases where a patient with oral cancer shows dysphagia, TS-1 may need to be tube-administered. Although tube administration by the simple suspension method has been recommended from a biosafety perspective, particularly for anti-cancer agents, its efficacy remains unclear. We established a simple high-performance liquid chromatography method for simultaneous determination of FT and 5-FU levels at clinical sites by modifying a method reported in the literature.1) Unlike the original method, this simplified method does not require extraction procedures to separate FT and 5-FU, and requires only 250 μl of serum. Using this method, we compared FT concentrations in the sera of oral cancer patients administered TS-1 orally or via a tube-assisted simple suspension method. No significant differences in FT concentrations were apparent between these two modes of administration. TS-1 treatment by tube administration using the simple suspension method thus seems useful for patients with dysphagia as an alternative to oral dosage.

TS‐1 enhances the effect of radiotherapy by suppressing radiation‐induced hypoxia‐inducible factor‐1 activation and inducing endothelial cell apoptosis

The therapeutic effect of concurrent chemoradiotherapy with TS-1 has been confirmed in various solid tumors; however, the detailed mechanism of action has not yet been fully elucidated. In the present study, we identified hypoxia-inducible factor-1 (HIF-1) as one of the targets of TS-1 in chemoradiotherapy. In growth delay assays using a tumor xenograft of non-small-cell lung carcinoma, H441, TS-1 treatment enhanced the therapeutic effect of single gamma-ray radiotherapy (14 Gy) and significantly delayed tumor growth by 1.58-fold compared to radiotherapy alone (P < 0.01). An optical in vivo imaging experiment using a HIF-1-dependent 5HRE-luc reporter gene revealed that TS-1 treatment suppressed radiation-induced activation of HIF-1 in the tumor xenografts. The suppression led to apoptosis of endothelial cells resulting in both a significant decrease in microvessel density (P < 0.05; vs radiation therapy alone) and a significant increase in apoptosis of tumor cells (P < 0.01; vs radiation therapy alone) in tumor xenografts. All of these results indicate that TS-1 enhances radiation-induced apoptosis of endothelial cells by suppressing HIF-1 activity, resulting in an increase in radiosensitivity of the tumor cells. Our findings strengthen the importance of both HIF-1 and its downstream gene, such as vascular endothelial cell growth factor, as therapeutic targets to enhance the effect of radiotherapy.

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

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

ＧＦＰ遺伝子導入ラット舌へん平上皮癌細胞株を用いた肺微小転移に対するＴＳ‐１の転移抑制効果

[Purpose] Lung metastases in patients with tongue cancer are resistant to various therapies, resulting in poor outcomes. In the present study, we examined whether such lung metastases are controllable by adjuvant chemotherapy targeting micrometastases in the lung. We used a micrometastasis model using a rat tongue carcinoma cell line (RSC3) tagged with the green fluorescent protein gene (RSC3LM-GFP) in nude mice.[Methods] Lung metastases were formed after intravenous (i. v.) injection of 1 (3)×105 tumor cells in a low (high) metastasis model. TS-1 (5-fluorouracil derivative)(20mg/kg) was orally administered from day 1 Postinjection (early administration) and from day 7 post-injection (late administration) 5 times per week for 3 weeks. Mice bearing lung metastases underwent autopsy 4 weeks after injection, and the lungs were removed. The numbers of lung metastases were determined by GFP fluorescence.[Results] Lung metastasis including micrometastasis could be clearly visualized under illumination with blue light. In the low metastasis model, GFP-positive metastatic nodules in the lung were more strongly reduced by early TS-1 oral administration than by late administration (p<0.003). Survival was also much longer in mice with early TS-1 treatment than in those with late treatment in the low metastasis model (p<0.02), but not in the high metastasis model.[Conclusion] These results indicate that the sensitivity of lung metastases of tongue carcinoma to TS-1 depends on the timing of drug administration and the number of metastases. Small numbers of micrometastases in the lung at an early stage are most susceptible and can be effectively eliminated by chemotherapy targeting micrometastasis, leading to longer survival of mice.