Stem cell therapy: social recognition recovery in a FASD model.

To better understand the cellular pathogenetic mechanisms of fetal alcohol spectrum disorder (FASD) and the therapeutic benefit of stem cell treatment, we exposed pregnant rats to ethanol followed by intravenous administration of neural stem cells (NSCs) complexed with atelocollagen to the new born rats and studied recovery of GABAergic interneuron numbers and synaptic protein density in the anterior cingulate cortex, hippocampus and amygdala. Prenatal ethanol exposure reduced both parvalbumin-positive phenotype of GABAergic interneurons and postsynaptic density protein 95 levels in these areas. Intravenous NSC treatment reversed these reductions. Furthermore, treatment with NSCs reversed impaired memory/cognitive function and social interaction behavior. These experiments underscore an important role for synaptic remodeling and GABAergic interneuron genesis in the pathophysiology and treatment of FASD and highlight the therapeutic potential for intravenous NSC administration in FASD utilizing atelocollagen.

Continuous infusion of 5-fluorouracil with versus without low-dose, consecutive administration of cisplatin in advanced colorectal cancer. A prospective randomized phase II study.

Recently, the treatment of advanced gastric cancer by continuous infusion of 5-fluorouracil (5-FU) with low-dose cisplatin (CDDP) has improved efficacy without severe toxicities. The possible effectiveness of 5-FU+low-dose CDDP for colorectal cancer (CRC) is intriguing. One hundred fifty-five patients with far-advanced CRC including at least one measurable lesion were enrolled in a prospective randomized clinical trial funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer. These patients were assigned to the two arms to assess the value of low-dose CDDP when added to a continuous intravenous infusion of 5-FU at a dose of 300 mg/m(2)/24 hrs in a one-week cycle consisting of 5 days of treatment and 2 days of rest for at least 12 weeks. CD-DP was given intravenously at a dose of 3 mg/m(2) on days 1-5 and days 8-12, and then at a dose of 7 mg/m(2) twice a week. Three patients were excluded from the trial. The response rate in the 5-FU+low-dose CDDP arm (n=75) was significantly higher than that in the 5-FU arm (n=77) (25.3% vs. 11.7%; P = 0.037). There was no significant difference in the median overall survival time between the 5-FU+low-dose CDDP arm and the 5-FU arm (479 and 491 days, respectively). Grades 3/4 toxicities occurred infrequently in both arms. The quality of life was almost the same between the arms. Low-dose CDDP improved the response rate while keeping toxicities within clinically acceptable limits. However, this combined treatment did not confer a survival advantage over treatment with continuous infusion of 5-FU alone for patients with far-advanced CRC; that might be attributable to the short CDDP administration setting of 12 weeks.

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.

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.

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.

Possible regulation of 5-fluorouracil-induced neuro- and oral toxicities by two biochemical modulators consisting of S-1, a new oral formulation of 5-fluorouracil.

S-1 is a new oral formulation of 5-fluorouracil (5-FU) containing 1 M tegafur and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) and 1 M potassium oxonate (Oxo). It has been reported to have a high antitumor activity and low gastrointestinal toxicity in rats bearing murine and human tumors. We further studied the possible inhibition of the toxicities caused by the products of 5-FU metabolism with the use of CDHP, a new inhibitor of 5-FU degradation and Oxo, an inhibitor of 5-FU phosphorylation. In a model of pentylenetetrazole-induced convulsions in mice, intravenous injection of fluoroacetate (3 mg/kg), 2-fluoro-b-alanine (30 mg/kg) and 5-FU (over 300 mg/kg) significantly augmented the occurrence of convulsion. However coadministration of an equivalent dose of CDHP with 5-FU almost completely suppressed the 5-FU-augmented convulsions, suggesting that inhibition of 5-FU catabolism by CDHP may lead to a decreased risk of development of 5-FU neurotoxicity. Another advantage of the use of S-1 was protection through Oxo against the development of 5-FU-induced mucositis, which occurs frequently in cancer patients. When 6 mg/kg of S-1 was administered orally to beagle dogs for 5 days, the incidence of stomatitis decreased markedly compared to that in dogs receiving the same dose of S-1 not containing Oxo, in which severe stomatitis was frequently observed. One of the possible mechanisms of the decreased incidence of mucositis associated with oral S-1 administration is the decreased formation of 5-fluoronucleotides from 5-FU in the mucosal tissues of the oral cavity. These results suggest that oral S-1 could be employed for the treatment of cancer patients with marked reduction in the incidence of toxicities including encephalopathy, stomatitis and diarrhea.

[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.

In vitro evaluation of experimental agents for anti-HIV activity.

This unit presents an assay that has proven useful as an initial screening test is an HIV cytopathic effect (CPE) inhibition assay in which immortalized T cell lines (e.g., ATH8 or MT2) that are profoundly sensitive to the cytopathic effect of certain strains of HIV are utilized as target cells. Additional protocols assess the anti-HIV activity of certain candidate agents by measuring inhibition of syncytium formation or p24 gag protein production by ELISA. Calculation of the 50% inhibitory concentration (IC(50)) is also presented.

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.

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.

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.

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.

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.

[Conceptual changes in cancer chemotherapy--biochemical modulation of 5-FU].

Recently, the demand for more useful therapies for cancer patients has increased. We describe in this paper a therapeutic modality based on a self-rescuing concept (SRC), and which features dual activity, i.e., an effect-enhancing activity and an 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: the oral fluoropyrimidine agent tegafur; a DPD inhibitor (CDHP) which is more potent than uracil, which is used in UFT; and an ORTC inhibitor (Oxo) which localizes in the gastrointestinal tract. S-1 is a combination drug with a molar ratio of 1:0.4:1 in FT, CDHP, and Oxo, respectively. A clinical pharmacology study was conducted to examine blood concentrations of 5-FU after twice-a-day administration of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were found to be 60 to 200 ng/ml in all twelve patients examined. The overall response rate was 44.6% (45/101). In addition, the incidence of adverse reactions judged to be grade 3 or higher was 10% or less. We have also reported a 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, i.v., 5 days/week), in which CDDP was used as a modulator of 5-FU. Low-dose FP therapy provided response rates as high as 40 to 60% in 163 patients with various gastrointestinal cancers other than pancreas cancer. The incidence of the adverse reactions of nausea and vomiting which were judged to be grade 3 or higher was 2.5% (4/163). The incidences of other adverse reactions were 1% or less. In line with the theory and practice of combination therapy with 5-FU (cvi) 24 hr cvi; 5-FU: 750 to 1,000 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 was utilized in which there was a difference in cell cycle between gastrointestinal mucosal cell and tumor cell, or between bone marrow cell and tumor cell. Few adverse reactions, e.g., diarrhea and stomatitis, were observed despite the overall response rate being as high as 52.4% (22/42). The incidence of adverse reaction judged to be grade 3 or higher was as low as 9.3% (5/54), with an incidence of 9.3% (5/54) in Grade 3 or higher myelotoxicity. We intend in the future to combine the abovementioned therapeutic modalities, which provoke fewer adverse reactions and are easy on patients with cancer in an effort to further increase their life expectancy.

[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.

An in vitro examination of a 5-fluorouracil regimen involving continuous venous infusion using cultured cell lines derived from ovarian cancers.

To examine the antitumor effectiveness of continuous venous infusion of 5-fluorouracil (5-FU), such a regimen was mimicked in vitro using cultured ovarian cancer cell lines. Two ovarian carcinoma cell lines, HRA and KK with cell doubling times (DT) of 16 h and 45 h, respectively, were grown under three incubation conditions with respect to 5-FU exposure, and the extent of growth inhibition was compared among the three conditions and between the two cell lines. Protocol I: 6 h-intermittent exposure to 5-FU, protocol II: 24 h-intermittent exposure to 5-FU, protocol III: uninterrupted exposure to 5-FU. The 50% growth inhibitory concentrations (IC50) of 5-FU obtained for KK cells grown under protocols I and II were both two times higher than that obtained under protocol III. Regarding HRA cells, IC50 obtained under protocol I was two times higher than that obtained under protocol III, while that obtained under protocol II was 3.7 times higher than that obtained under protocol III. Results obtained from the present in vitro examination suggested that the drug-free interval in the intermittent infusion of 5-FU should be shorter than the DT of the targeted tumor cells to obtain an efficacy corresponding to that obtained by uninterrupted exposure to the drug. In establishing an effective intermittent continuous infusion therapy with 5-FU with fewer side effects, the drug-free interval should be shorter than the DT of tumor cells, but longer than the DT of proliferating cells in normal tissues, including gastrointestinal mucosa cells assuming that these normal cells possess shorter DT than tumor cells.

[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.

Self-Assembly of a Radially Functionalized Hexagonal Molecule: Hexakis(4-hydroxyphenyl)benzene.

Two different porous hydrogen-bonded networks are formed by self-assembly of the radially substituted host 1. In the network of type A, formed by 1 small middle dot4 Et(2)O, all OH groups of 1 are involved in hydrogen bonding, and the molecular sheets are stacked without translation to generate extended channels that accommodate the Et(2)O molecules. Four OH groups of 1 are involved in the type B network of 1 small middle dot4 DMF, and lateral translation of the sheets in an ABAB sequence generates large chambers, each of which contains four DMF molecules.

[Low-dose FP therapy for advanced and recurrent gastric cancer].

Continuous infusion of 5-FU and low-dose CDDP infusion (low-dose FP therapy) is one of the effective combination chemotherapies for advanced and recurrent gastric cancer. Several studies have reported low-dose FP therapy showed high response rates (40-50%) and a low incidence of toxicities. There was a positive correlation between antitumor effect and survival time on neoadjuvant chemotherapy for advanced gastric cancer. It still may be necessary to improve quality of life by changing the regimen of low-dose FP therapy because patients require hospitalization for the therapy.