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T Shirasaka

Publications and source records attributed to T Shirasaka.

At least 19 recordsLinked to original sources
PubMed2006

Moderate neutropenia with S-1 plus low-dose cisplatin may predict a more favourable prognosis in advanced gastric cancer.

AIMS: The effects of haematological adverse events on the prognosis of patients with gastric cancer were investigated. MATERIALS AND METHODS: We retrospectively analysed the association between haematological adverse events and prognosis in 23 patients with far advanced or recurrent gastric cancer treated with a JFMC27-9902 regimen consisting of an oral fluorouracil derivative S-1 plus low-dose cisplatin. RESULTS: The patients who suffered grade 2-3 neutropenia (n = 10; median survival time [MST] 679 days) were found to have significantly more favourable prognoses than patients who developed grade 0-1 (n = 10; MST 271 days) or grade 4 neutropenia (n = 3; MST 408 days) (P = 0.0039 and 0.0112, respectively), although no significant differences were found among the clinicopathological factors of any grade groups. With respect to anaemia or thrombocytopenia, there were no significant differences among the MSTs of the groups stratified by toxicity grade. Multivariate survival analysis revealed that grade 2-3 neutropenia is an independent predictor of a more favourable prognosis (hazard ratio = 38.693, P = 0.0004). CONCLUSIONS: These results suggest that S-1 plus low-dose cisplatin against gastric cancer may contribute to long survival when it induces moderate neutropenia.

Adult↗
PubMed2006

Transplatin, a cisplatin trans-isomer, may enhance the anticancer effect of 5-fluorouracil.

Transplatin (TDDP), a trans-isomer of cisplatin (CDDP), is well known to have faint cytotoxicity because its geometric structure allows less adduct formation with DNA than does CDDP. However, TDDP might have the potential to enhance the anticancer effect of 5-fluorouracil (5-FU) as well as CDDP. In this study, five gastric cancer cell lines were used. Cells were treated with 5-FU, TDDP, TDDP+5-FU, CDDP, and CDDP+5-FU, for 72 hrs. Synergistic effects between TDDP and 5-FU were observed in OCUM-2MD3, OCUM-2M, and OCUM-11, though they were not observed in MKN-45 or MKN-28. The cell lines in which synergistic effects were observed between TDDP and 5-FU were the same ones in which synergistic effects are shown between CDDP and 5-FU. The cell lines without synergism between 5-FU +TDDP/CDDP had lower thymidylate synthase (TS) activities than those with synergism, suggesting TS might be attributable to the synergistic mechanism. TDDP alone, compared to CDDP alone, gave rather low cytotoxicity for these cell lines. In conclusion, TDDP might be a clinically useful modulator of 5-FU.

Antimetabolites, Antineoplastic↗
PubMed2003

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.

Animals↗
PubMed2001

Nociceptin/orphanin FQ and [Phe(1)psi(CH2-NH)Gly2]nociceptin(1-13)NH2 modulates the activity of hypothalamic paraventricular nucleus neurons in vitro.

Nociceptin, also known as orphanin FQ (N/OFQ), an endogenous ligand for the orphan opioid receptor-like(1) (ORL(1)) receptor, is moderately expressed in the hypothalamic paraventricular nucleus (PVN) involved in the integrative control of the function of the endocrine and autonomic nervous systems. Our previous study demonstrated that intracerebroventricular administration of N/OFQ elicits an inhibitory action on the function of the cardiovascular and sympathetic nervous systems in conscious rats. However, the effects of N/OFQ on PVN neurons have not been examined. We investigated the effects of N/OFQ on PVN neurons using a whole-cell patch-clamp recording technique in rat brain slices. N/OFQ (30-1000 nM) hyperpolarized membrane potentials in type 1 and type 2 neurons of the PVN classified by the electrophysiological property. [Phe(1)psi(CH2-NH)Gly2]nociceptin(1-13)NH2 (Phepsi) (1-9 microM), a presumed competitive antagonist of the ORL(1) receptor, also hyperpolarized membrane potential in both types of neurons. In voltage clamp studies, N/OFQ (3-3000 nM) activated a K+ current concentration-dependently in 69.7% of PVN neurons with an EC(50) of 72.4+/-12 nM. Phepsi (100-9000 nM) also activated a K+ current with an EC(50) of 818+/-162 nM in PVN neurons, and significantly reduced the amplitude of the N/OFQ-stimulated current. The N/OFQ-induced current was not antagonized by the classical opioid receptor antagonist naloxone and putative antagonist nocistatin. These findings suggest that N/OFQ may have a functional role in the PVN.

Animals↗
PubMed2001

No evidence of persistent mumps virus infection in inflammatory bowel disease.

BACKGROUND AND AIM: There is controversy regarding whether paramyxovirus infection is causally associated with inflammatory bowel disease (IBD). The latest cohort study claimed that atypical measles and mumps infections in childhood may be risk factors for later IBD. This study was conducted to clarify the validity of a causal link between persistent mumps virus infection and IBD. SUBJECTS AND METHODS: (1) Amplification of the mumps virus genome was performed in both intestinal specimens (ulcerative colitis 15, Crohn's disease 15, control 10) and peripheral blood lymphocytes (PBL) (ulcerative colitis seven, Crohn's disease six, control three) by reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern hybridisation using primers specific to the viral genome encoding phosphoprotein or haemagglutinin-neuraminidase. (2) Titre of serum antimumps IgG was measured in 16 patients with ulcerative colitis, in 16 patients with Crohn's disease, and in 16 normal controls using an enzyme linked immunosorbent assay. RESULTS: (1) The mumps virus genome was not detected by RT-PCR in intestinal specimens or PBL in any case. (2) Antimumps IgG titre was positive in 7/16 ulcerative colitis, 10/16 Crohn's disease, and 11/16 control specimens. The mean (SEM) titre of antimumps IgG was 12.281 (7.831) in ulcerative colitis, 7.675 (1.608) in Crohn's disease, and 8.637 (1.969) in controls, with no significant difference between the three groups. CONCLUSION: We could not find any evidence to support a causal link between persistent mumps virus infection and IBD.

Adolescent↗
PubMed2001

Orexin depolarizes rat hypothalamic paraventricular nucleus neurons.

Orexins, also called hypocretins, are newly discovered hypothalamic peptides that are thought to be involved in various physiological functions. In spite of the fact that orexin receptors, especially orexin receptor 2, are abundant in the hypothalamic paraventricular nucleus (PVN), the effects of orexins on PVN neurons remain unknown. Using a whole cell patch-clamp recording technique, we investigated the effects of orexin-B on PVN neurons of rat brain slices. Bath application of orexin-B (0.01-1.0 microM) depolarized 80.8% of type 1 (n = 26) and 79.2% of type 2 neurons tested (n = 24) in the PVN in a concentration-dependent manner. The effects of orexin-B persisted in the presence of TTX (1 microM), indicating that these depolarizing effects were generated postsynaptically. Addition of Cd(2+) (1 mM) to artificial cerebrospinal fluid containing TTX (1 microM) significantly reduced the depolarizing effect in type 2 neurons. These results suggest that orexin-B has excitatory effects on the PVN neurons mediated via a depolarization of the membrane potential.

Animals↗
PubMed2001

[New oral anticancer drug, TS-1 (S-1)--from bench to clinic].

We describe in this paper a therapeutic modality which is based on a self-rescuing concept (SRC) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent, tegafur (FT); a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT; and an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract. We devised a novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively. To compare S-1, FT, and UFT in terms of their anticancer activity and adverse reactions, a colon cancer implantation model in rats was used for 4-week consecutive oral administration from the time when the postimplantation tumor weight become about 2 g. The tumor disappeared on day 16 at a given dose of S-1 (as 22.5 mg/kg FT), and the tumor did not reappear for at least three months. Antitumor activity was more marked with S-1 than FT and UFT. Adverse reaction, i.e., stomatitis, depilation, and weight loss, were less frequent in the S-1 group than in the other groups. A clinical pharmacology study examined blood concentrations of 5-FU after twice-a-day administration after meals of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were 60 to 200 ng/ml in all twelve patients examined. Late phase II clinical trials of S-1 were conducted in patients with advanced and recurrent stomach cancers, in the same regimen as for the clinical pharmacology study. It basically consisted in four cycles, each of which comprised 4-week, twice-a-day, consecutive oral administration with a 2-week withdrawal. The overall response rate was 44.6% (45/101). Median survival time (MST) was 224 days. S-1 was given manufacturing approval by the Ministry of Health and Welfare of Japan after a priority review, with indications for advanced and recurrent stomach cancers. A late phase II clinical study of S-1 in patients with advanced/recurrent head and neck cancer was conducted in 59 eligible patients. Objective responses were 4 complete response (CR) and 13 partial response (PR), for a response rate of 28.8% (17/59). MST was 344 days. Grade 4 hemoglobin decrease was observed in one case; however, this returned to normal after the termination of drug administration and blood transfusion. Therefore, this event was confirmed to be reversible. A late phase II clinical trial of S-1 was conducted to evaluate the efficacy and toxicities in patients with metastatic colorectal carcinoma. Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled in this clinical trial. The overall response rate was 35.5% (22/62), and the MST was 378 days. The main adverse reactions were myelosuppression and GI toxicities. The incidence of neutropenia (Grade 3 or 4) was 13%, while the incidence of other adverse reactions was 10% or below. None of 53 outpatients required to be hospitalization due to adverse reactions. Late phase II clinical trials of S-1 are in progress for colorectal cancer, breast cancer and non-small cell lung cancer. To establish the standard therapeutic modality for cancers, including gastrointestinal cancers, in Japan, the conduction of clinical trials combining S-1 and other anticancer drugs holds promise for the future.

Administration, Oral↗
PubMed2000

Tridurylboranes extended by three arylethynyl groups as a new family of boron-based pi-electron systems

A series of tris(phenylethynylduryl)boranes (R-C(6)H(4)-C&tbd1;C-duryl)(3)B with various substituents R have been prepared as air-stable solids owing to the steric protection of the boron atom by the three bulky duryl groups. These compounds show unique photophysical properties due to the p(pi)-pi conjugation through the p-orbital on the boron atom. In particular, a push-pull type derivative with R = NMe(2) exhibits a significant solvatochromism of fluorescence from blue to orange colors.

Journal Article↗
PubMed2000

Effect of consecutive lower-dose cisplatin in enhancement of 5-fluorouracil cytotoxicity in experimental tumor cells in vivo.

It is known that cisplatin (CDDP) potentiates the cytotoxicity of 5-fluorouracil (5-FU), and that the biochemical mechanism is an increase in the intracellular reduced folate levels in the tumor cells. We investigated the effect of consecutive administration with lower-dose CDDP on intracellular accumulation of reduced folate and the activity of methionine synthase, a key enzyme in intracellular methionine synthesis. When CDDP (1 mg/kg) was administered i.p. to ascitic Yoshida sarcoma-bearing rats for 4 consecutive days, both the reduced folate levels and methionine synthase activity in the cells significantly increased, as the same as a single 5 mg/kg dose of CDDP. Furthermore, when Yoshida sarcoma-bearing rats were pre-treated with 1 mg/kg CDDP for 5 consecutive days, [14C]L-methionine incorporation into the isolated ascitic cells was significantly inhibited as compared to that in non-treated cells, suggesting that consecutive administration of lower-dose CDDP is capable of inducing the intracellular modulation of reduced folate levels and methionine synthase activity via inhibition of cellular uptake of methionine. In addition, 5-day administration of lower-dose (1 mg/kg) CDDP potentiated the antitumor effect of 5 mg/kg S-1, a new oral preparation of tegafur, given for 7 consecutive days, and this combined effect was almost similar to the antitumor effect of a combination of S-1 and a single conventional dose (5 mg/kg) of CDDP. Consecutive lower-dose CDDP also may be concluded to act as an important modulator of the enhancement of 5-FU cytotoxicity in experimental tumors.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2000

The MMR question.

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Antigens, Viral↗
PubMed2000

Conceptual changes in cancer chemotherapy: from an oral fluoropyrimidine prodrug, UFT, to a novel oral fluoropyrimidine prodrug, S-1, and low-dose FP therapy in Japan.

The conventional concept in cancer chemotherapy considers that no efficacy can be attained without provoking adverse reactions. We presented concrete descriptions based on a novel concept allowing us to emerge from the old one. Relief of adverse reactions, e.g., diarrhea, stomatitis, anorexia, and H&F syndrome, not only improves QOL of the patient but also allows prolongation of the treatment period without lowering patient compliance. We describe in this paper a therapeutic modality which is based on SRC (self-rescuing concept) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent tegafur; a DPD inhibitor (CDHP) which is more potent than uracil used in UFT; and an ORTC inhibitor (Oxo) which localizes in the gastrointestinal tract. Furthermore, we refer to combination therapy with 5-FU (CIV) and low-dose consecutive CDDP in which CDDP was used as a modulator of 5-FU and to the theory and practice of combination therapy with 5-FU (CVI) intermittent (Monday, Wednesday, and Friday) administration and low-dose CDDP consecutive administration in which a difference in cell cycle between gastrointestinal mucosal cell and tumor cell or between bone marrow cell and tumor cell was utilized. We intend in future to combine the abovementioned therapeutic modalities provoking less adverse reactions and being gentle to patients with cancer in an effort to further increase their life expectancy.

Administration, Oral↗
PubMed2000

[Preliminary clinical evaluation of low-dose CDDP and continuous 5-FU therapy for advanced gallbladder cancer].

5-fluorouracil (5-FU) has been widely used for the treatment of gastrointestinal cancers. Low-dose cisplatin (CDDP) and continuous venous infusion of 5-FU have recently shown additive or synergistic antitumor effects in experimental models. In this study, we evaluated the clinical effects of low-dose CDDP and 5-FU (low-dose FP therapy) in patients with advanced gallbladder cancer. From December, 1993 to June, 1998, 13 patients with advanced gallbladder cancer were treated with low-dose FP therapy. Patients were eligible for this study if they had a bidimensionally measurable tumor. 5-FU (160 mg/m2/day) was continuously infused over 24 hours using an implantable port, and CDDP (3 mg/m2/day) was infused for one hour. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest, each for four weeks according to response and tolerance. Low-dose FP therapy was given to 12 patients (92.3%). The response rate was 66.7% and the median survival time was 151 days. The regimen was tolerable, with the most common toxicity being nausea (38.5%). There were no severe side effects except for one patient who suffered from grade 3 nausea. We conclude that low-dose FP therapy may be useful as a palliative chemotherapy for cases of advanced gallbladder cancer.

Aged↗
PubMed2000

[Combined effect of S-1 and CDDP as a modulator for colon 26 liver metastasis].

S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo) in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-fluorouracil (5-FU). In this study the combined effect of S-1 and low-dose CDDP as a modulator for colon 26 liver metastasis in mice was evaluated. In an experiment with S-1 (5 mg/kg/day: po) and CDDP (0.25 mg/kg/day: i.p.) for 14 days, the combined effects for both liver metastasis and tumor of spleen were not superior to those with S-1 or CDDP alone group. Body weight loss was not greater in the S-1 + CDDP group than in the control group. In an experiment with S-1 (5 mg x 2/kg/day: po) and CDDP (0.25 mg/kg/day: i.p.) for 7 days, the inhibitory effects of S-1 + CDDP of liver metastasis and tumor of the spleen were remarkable compared with the S-1 alone group. However a greater loss of body weight was seen in the S-1 + CDDP group than in other groups. This study suggests that low-dose CDDP might be a modulator of S-1 for colon 26 liver metastasis. Further study is needed to determine the optimum dose and duration of treatment.

Animals↗
PubMed2000

Conceptual changes in cancer chemotherapy--biochemical modulation of 5-FU from bench to clinic.

Recently, a demand for therapy of higher usefulness in cancer patients has increased. We described in this paper a therapeutic modality which is based on SRC (self-rescuing concept) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We presented the theory and practice of S-1, a novel oral fluoropyrimidine anti-cancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent tegafur; a DPD inhibitor (CDHP) which is more potent than uracil used in UFT; and an ORTC inhibitor (Oxo) which localizes in the gastrointestinal tract. S-1, as a combination drug with a molar ratio of 1:0.4:1 in FT, CDHP, and Oxo, respectively. A clinical pharmacology study to examine blood concentrations of 5-FU after twice-a-day administration of S-1 at a dose 40 mg/m2. Consequently , blood concentrations of 5-FU were 60 to 200 ng/m/ in all twelve patients examined. The overall response rate was 44.6% (45/101). In addition, the incidence of adverse reactions judged to be G3 or higher was 10% or less. Furthermore, we referred to combination therapy with 5-FU (CIV)(5-FU: 250 to 350 mg/body, 24-hour CVI, consecutive days) and low-dose cisplatin (CDDP: 3 to 5 mg/body, iv, 5 days/week) in which CDDP was used as modulator of 5-FU. Low-dose FP therapy provided response rates as high as 40 to 60% in 163 patients with sorts of gastrointestinal cancers except pancreas cancer. The incidence of adverse reactions which were judged to be G3 or higher was 2.5% (4/163) in nausea and vomiting. The incidences of other adverse reactions were 1% or less. And to the theory and practice of combination therapy with 5-FU (CVI) 24-hour CVI; 5-FU: 750 to 1000 mg/body/day on Monday, Wednesday, and Friday; withdrawal on Tuesday, Thursday, Saturday, and Sunday) intermittent administration and low-dose CDDP (3 to 5 mg/body/day day 1-5/w) consecutive administration in which a difference in cell cycle between gastrointestinal mucosal cel l and tumor cell or between bone marrow cell and tumor cell was utilized . Little adverse reactions, e.g., diarrhea and stomatitis, were observed despite the overall response rate which was as high as 52.4% (22/42). We intend in the future to combine the above mentioned therapeutic modalities provoking less adverse reactions and being gentle to patients with cancer in an effort to further increase their life expectancy.

Administration, Oral↗
PubMed2000

Combination chemotherapy of continuous 5-FU infusion and low-dose cisplatin infusion for the treatment of advanced and recurrent gastric and colorectal adenocarcinomas.

We evaluate the efficacy and toxicities of low-dose FP therapy in the treatment of advanced and recurrent gastric and colorectal adenocarcinomas. 104 patients (gastric adenocarcinoma: 52, colorectal adenocarcinoma: 52) were enrolled. Low-dose FP therapy consisted of 5-FU (160 mg/m2/day every day by continuous infusion) and cisplatin (3 mg/m2/day in 100 ml of normal saline by infusion over 30 minutes on days 1-5/W). Patients were treated for 4 consecutive weeks with subsequent one-week rest period. Ninety-four of 104 patients completed this therapy, and the treatment accomplishment rate was 90%; 82% in gastric adenocarcinomas, 96% in colorectal adenocarcinomas. Two cases had CR, and 47 cases had PR, with an overall response rate of 52.1%. Response rates, 50% survival time, 1-year survival rates, and 2-year survival rates were 65.9%, 249 days, 33.7%, 19.7% in gastric adenocarcinomas, and 40.0%, 466 days, 56.7%, 29.4% in colorectal adenocarcinomas, respectively. Nausea/vomiting was the most common toxicity, occurring in 44.2% of patients treated and was predominantly mild to moderate (up to Grade 2). In 5 cases Grade 3 toxicity was observed. Low-dose FP therapy has a high antineoplastic effect and low-grade toxicity, and this therapy should become the first-choice chemotherapy for the treatment of advanced and recurrent gastric and colorectal adenocarcinomas.

Adenocarcinoma↗
PubMed2000

The role of low dose cisplatin plus 5-fluorouracil for treatment of recurrent and/or advanced squamous cell carcinoma of the head and neck.

To improve survival rate in advanced head and neck cancer, we scheduled 90 patients to receive low dose cisplatin plus 5-fluorouracil regimen as neoadjuvant(NAC), concurrent(CC), adjuvant(AC), and second line chemotherapy (SC) setting. Our regimen consisted of cisplatin (CDDP 5 mg/m2/1 hr infusion on days 1-5, 8-12, 15-19, 22-26) and 5-fluorouracil (5-FU 200 mg/m2/24 hr infusion or oral administration of tegaful-uracil (UFT-E) 400 mg/body on days 1-28). The concurrent chemoradiotherapy consisted of conventional irradiation with 1.6-2.0 Gy/day on five days per week up to a total dose around 60Gy, and CDDP 3 mg/m2 by intravenous infusion over 1 hour plus 5-FU 150 mg/m2 by intravenous infusion over 24 hours per day on five days per week. For SC, 24 patients evaluable for response, 4 CR and 6 PR with RR of 42% were achieved. For NAC, 14 patients were evaluated for response, 2 CR and 7 PR were achieved. CC was indicated for locally unresectable cases. Of the 33 patients evaluable for response were 17 CR and 9 PR with RR of 79%. Dose limiting toxicities for chemotherapy were anemia and leukopenia and chemoradiotherapy was mucositis. Our treatment modality showed marginal toxicity and good response. Moreover, our regimen could be given in an outpatient setting safely so quality of life for patients was identical. We concluded that for advanced head and neck cancer, these treatment options were effective for second line and adjuvant setting. Chemoradiotherapy with this regimen also gave a impact for improving local control and survival period for locally unresectable cases.

Adult↗