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Biomedical subjects

T Taguchi

Publications and source records attributed to T Taguchi.

At least 127 records · Page 7Linked to original sources

[A phase I study of DWA2114R].

Phase I study of DWA2114R, a new platinum analogue, was conducted in 39 patients with various tumor types by a group of 13 institutions. Of the 39 patients entered in this study, 35 were evaluable. The starting dose was 40 mg/m2 (1N) and the drug was administered i.v. for 20-30 min, escalating stepwisely up to 1,000 mg/m2 (25 N). The dose limiting factor (DLF) was leukocytopenia, especially neutrocytopenia, and the maximum tolerated dose (MTD) was more than 1,000 mg/m2. Major clinical toxicity was gastrointestinal. Hepatotoxicity and nephrotoxicity were mild. Following administration of the drug, plasma concentrations of total and filterable platinum (Pt) showed a triphasic and biphasic decays. Excretion into urine within 24 hours was in the range of 54.2% to 92.2% of the administered platinum. The recommended dose of phase II study was 800-1,000 mg/m2, repeating every 3-4 weeks.

Adult

[Phase I study of a new platinum complex 254-S, cis-diammine (glycolato)-platinum (II)].

A new platinum complex 254-S had a superior preclinical therapeutic indices compared to cisplatin, showing decreased renal and gastrointestinal toxicities. Phase I clinical study with a single dose schedule was conducted to investigate the safety, toxicity, pharmacokinetics and possible efficacy against various advanced cancers by a cooperative study of 10 institutions. The drug was administered by i.v. infusion for 60 min dissolved in 250 ml of 5% xylitol solution, without the use of hydration and antiemetics. At least 3 patients at each dose level of 10, 20, 40, 80, 100 and 120 mg/m2 were tested and 28 patients were entered into this study. Myelosuppression, especially thrombocytopenia, appeared strongly at dose level of 80 mg/m2 and dose limiting thrombocytopenia was found in 2 of 5 patients. Leukocytopenia was also dose-related but moderate. Platelet and WBC nadirs occurred around 3 weeks after administration with recovery in about one week. Although slight elevation of BUN and creatinine were temporarily observed in a few cases, no significant renal toxicity was observed. Anorexia, nausea and vomiting were observed in the majority of patients, but milder than cisplatin. In conclusion, 254-S has demonstrated reduced non-hematologic toxicities as compared to cisplatin. This drug appears to be well tolerated and 120 mg/m2 was maximum tolerated dose. The recommended dose for phase II studies was thought to be 100 mg/m2 by i.v. infusion every 4 weeks.

Adult

[A phase II clinical study of cis-diammine glycolato platinum, 254-S, for advanced breast cancer].

A phase II clinical study of 254-S, a new anticancer platinum complex for advanced breast cancer, was conducted by the 254-S Breast Cancer Study Group consisting of 6 institutions nation-wide. Considering the results of the phase I clinical study, 254-S was administered at 100 mg/m2 by intravenous drip infusion and this administration was repeated at least 2 times at 4-week intervals. Of 19 patients registered, 16 were evaluable for tumor response (complete cases). Partial response (PR) was obtained in 2 patients, for a 12.5% response rate. Major toxic effects observed were hematotoxicity thrombocytopenia and leukopenia, and gastrointestinal toxicity (nausea and vomiting, and anorexia), though there was no case in which the treatment with 254-S had to be discontinued due to the toxic effect.

Aged

Novel function for intestinal intraepithelial lymphocytes. Murine CD3+, gamma/delta TCR+ T cells produce IFN-gamma and IL-5.

Intestinal intraepithelial lymphocytes (IEL) from mice are greater than 80% CD3+ T cells and could be separated into four subsets according to expression of CD4 and CD8. In our studies designed to assess the functions of IEL, namely, cytokine production, it was important to initially characterize the various subsets of T cells that reside in IEL. The major subset was CD4-, CD8+ (75% of CD3+ T cells), which contained approximately 45 to 65% gamma/delta TCR+ and 35 to 45% alpha/beta TCR+ T cells. Approximately 7.5% of IEL T cells were CD4-, CD8- (double negative) and gamma/delta+ population. On the other hand, CD4+, CD8+ (double positive) and CD4+, CD8- fractions represented 10% and 7.5% of CD3+ T cells, respectively, which were all alpha/beta TCR+. Inasmuch as CD3+, CD4-, CD8+ T cells are a major subset of IEL which contain both gamma/delta TCR or alpha/beta TCR-bearing cells, the present study was focused on the capability of this subset of IEL T cells to produce the cytokines IFN-gamma and IL-5. Both gamma/delta TCR+ and alpha/beta TCR+ IEL spontaneously produced IFN-gamma and IL-5, although higher frequencies of cytokine spot-forming cells were associated with the alpha/beta TCR+ subset. Approximately 30% of CD8+, gamma/delta TCR+ cells produced both cytokines, whereas approximately 90% of alpha/beta TCR+ T cells produced either IFN-gamma or IL-5. Both gamma/delta TCR+ and alpha/beta TCR+ IEL possessed large quantities of cytokine-specific mRNA, clearly showing that these IEL were programmed for cytokine production. When IEL were activated with anti-gamma/delta or anti-CD8 antibodies, higher numbers of IFN-gamma and IL-5 spot-forming cells were noted. The present study has provided direct evidence that a major function of IEL involves cytokine production, and this is the first evidence that gamma/delta TCR+ cells in IEL possess the capability of producing both IL-5 and IFN-gamma.

Animals

Purification of a K(+)-channel protein of sarcoplasmic reticulum by assaying the channel activity in the planar lipid bilayer system.

A K(+)-channel protein of the sarcoplasmic reticulum (SR) was purified by assaying the channel activity in a planar lipid bilayer system. The light fraction of SR vesicles was solubilized in 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and fractionated by an anion-exchange chromatography and followed by gel filtration chromatography and affinity chromatography with concanavalin A. All fractions in each steps were mixed with asolectin solubilized in CHAPS and reconstituted into vesicles by dialysis. The channel activity of each fraction was assayed after the reconstituted vesicles had been fused into a planar lipid bilayer. The final fraction which showed the K(+)-channel activity contained only 100 kDa protein in a silver-stained gel after SDS-PAGE and an anti-Ca(2+)-ATPase antibody did not recognize the protein. The characteristics of the K(+)-channel were identical to those observed in native SR vesicles when using the same method. The channel showed a single-channel conductance of 120 pS in 0.1 M KCl and marked voltage dependence. The channel did not permeate Ca2+ and Cl- and was blocked by neomycin B.

Animals

Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.

Aged

Purification of a Cl-(-)channel protein of sarcoplasmic reticulum by assaying the channel activity in the planar lipid bilayer system.

A Cl- channel protein of sarcoplasmic reticulum (SR) was purified by assaying the channel activity in a planar lipid bilayer system. The light fraction of SR vesicles was solubilized in CHAPS and fractioned by anion exchange, gel filtration, and affinity chromatography with concanavalin A. All fractions in each step were reconstituted into vesicles with asolectin by dialysis and their channel activities were assayed after the vesicles had been fused into a planar lipid bilayer. A 100-kDa protein, different from Ca2(+)-ATPase, was found to form anion channels.

Animals

Structural and functional characterization of inositol 1,4,5-trisphosphate receptor channel from mouse cerebellum.

The cerebellar inositol 1,4,5-trisphosphate (InsP3) receptor is a high molecular weight glycoprotein abundantly expressed in Purkinje cells. The subunit structure of the InsP3 receptor protein was examined by cross-linking experiments. Agarose-polyacrylamide gel electrophoresis of the cross-linked materials demonstrated that the cerebellar InsP3 receptor protein is composed of four noncovalently bound identical subunits each with a Mr of 320,000 in both purified and microsome-bound states. Chromatography of the purified receptor on a calmodulin-Sepharose column demonstrated a Ca2(+)-dependent interaction of the InsP3 receptor with calmodulin. Photoaffinity labeling of the cerebellar microsomal fraction with [alpha-32P]8-azidoadenosine 5'-triphosphate revealed the presence of ATP-binding site in the InsP3 receptor. Scatchard analysis of the purified InsP3 receptor revealed the Bmax and Kd values for ATP binding of 2.3 pmol/micrograms and 17 microM, respectively. Reconstitution of the purified InsP3 receptor into the planar lipid bilayer indicated channel activity in the purified receptor. It exhibited a calcium conductance (26 pS in 53 mM Ca2+) and sodium conductance (21 pS in 100-500 mM asymmetric Na+ solutions) with permeability ratios of PCa/PTris = 6.3 and PNa/PCl = 5.4. The purified channel was activated with submillimolar ATP in the presence of InsP3 and modified to reach a large conductance state.

Affinity Labels

Quantitation of urinary chlorobenzene metabolites by HPLC: concentrations of 4-chlorocatechol and chlorophenols in urine and of chlorobenzene in biological specimens of subjects exposed to chlorobenzene.

A simple method for the determination of 4-chlorocatechol (ClCh, 4-chloro-1,2-benzenediol) and chlorophenols (ClPh), metabolites of monochlorobenzene (ClBz), in urine by high performance liquid chromatography (HPLC) is described. Enzymatic hydrolysates of urine were applied to a stainless-steel column packed with octadecyl-silanized silica gel, and a mixed solution of 20 mM potassium phosphate monobasic: acetonitryl (75:25, v/v) was used as a mobile phase. The procedures for ether extraction and evaporation of extract could be omitted. The accuracy and precision of the present HPLC method were satisfactory. The excretion kinetics of ClCh and p-ClPh were investigated over 35 h after cessation of ClBz inhalation. Proportional relationships between concentrations of ClBz in air and of its metabolites in urine were observed. The slopes of regression lines predicting the levels of ClCh, p-ClPh and total ClPh in urine taken during the last 2 h of exposure to ClBz in air were 6.56, 1.13 and 2.83 mg/g creatinine for 1 ppm ClBz, respectively. ClBz in the blood and the end exhaled air of subjects at the end of exposure were identified by gas chromatography (GC) and mass spectrometry. A proportional relationship was observed between the concentration of ClBz in air and that in blood. The validity of the threshold limit value (TLV) for ClBz as evaluated from the subjective and objective symptoms is discussed.

Adult

Urinary 2,5-hexanedione assay involving its conversion to 2,5-dimethylpyrrole.

High-performance liquid chromatography (HPLC), gas chromatography (GC) and spectrophotometry were used to examine 2,5-dimethylpyrrole, derived from 2,5-hexanedione in the acid-hydrolyzed urine of subjects exposed to n-hexane. The urine of a subject exposed to n-hexane was hydrolyzed with hydrochloric acid and then neutralized. Thereafter, 2,5-hexanedione in the hydrolysate was heated with ammonium carbonate to yield 2,5-dimethylpyrrole. A methanol extract of the 2,5-dimethylpyrrole formed was subjected to HPLC and an ethylacetate extract of it was subjected to GC, with a flame thermoionic detector (FTD). For spectrophotometry, the ethylacetate extract was allowed to react with Ehrlich's reagent and then the absorbance of the colored compound formed was read at 525 nm. Pyrrole condensation with ammonia is specific to 1,4-diketones and these three assay methods can be used for determination of 2,5-hexanedione in the urine of workers exposed to n-hexane. The hydrolytic conditions for urine of subjects exposed to n-hexane for analysis of 2,5-hexanedione were discussed.

Benzaldehydes

Antitumor activity on murine tumors of a novel antitumor benzoylphenylurea derivative, HO-221.

A novel antitumor compound, N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea (HO-221) was evaluated for its antitumor activity in experimental tumor models. HO-221 preparation was given orally to tumor-bearing animals. The compound exhibited significant effects against various tumors such as P388 and L1210 leukemias; M5076 reticulum-cell sarcoma; colon 38 carcinoma; human xenografts MX-1, LX-1, GA-1, and Co-1; Lewis lung carcinoma; sarcoma 180; and Walker 256 carcinosarcoma and was especially effective against solid tumors. However, its effect on murine B16 melanoma was moderate. Intermittent administration of HO-221 produced better results. The effects of HO-221 on human tumor xenografts were compared with those of other antitumor agents. HO-221 showed activity against LX-1 lung and Co-1 gastrointestinal tumor and was also effective against advanced-stage L1210 leukemia and Lewis lung carcinoma. Furthermore, the effect of HO-221 on drug-resistant tumors was examined using murine leukemias L1210 and P388. It showed no cross-resistance with the known antitumor agents Adriamycin (ADM), daunomycin (DM), vincristine (VCR), mitomycin C (MMC), cisplatin (CDDP), 5-fluorouracil (5-FU), cytosine arabinoside (Ara-C), methotrexate (MTX), cyclophosphamide (CPA), or carboquone (CQ), and collateral sensitivity to HO-221 was found in MMC-, CDDP-, and CPA-resistant sublines. HO-221 exhibits significant reproducible, broad-spectrum antitumor activity against experimental tumors as well as human neoplasms.

Animals

Immunohistochemical study of colorectal adenocarcinomas and adenomas with antibodies against carcinoembryonic antigen (CEA), CA19-9, keratin, alpha-tubulin and secretory component (SC).

The immunohistochemical localization of five antibodies against carcinoembryonic antigen (CEA), CA19-9, keratin, alpha-tubulin and secretory component (SC) was investigated in 14 lesions of adenocarcinoma (AC), 22 of adenoma with high-grade atypia (AH), 50 of adenoma with low-grade atypia (AL), and 15 of non-neoplastic mucosa (NNM) of the large intestine. The positive patterns for each staining were divided into three categories (patterns 1, 2, and 3). All neoplastic lesions (AC, AH and AL) were positive for CEA, while 85.7% of AC, 36.4% of AH and 6.0% of AL showed strongly positive staining (pattern 3). 78.6% of AC and 54.5% of AH were positive for CA19-9 in comparison to 20.0% of AL. For keratin, more than 95% of the neoplastic lesions were positive, while 78.6% of AC, 27.3% of AH and 22.0% of AL showed strongly positive staining (pattern 3). For alpha-tubulin, more than 85% of neoplastic lesions were positive, while 50.0% of AC, 36.3% of AH and 26.0% of AL showed strongly positive staining (pattern 3). For SC, in contrast, 42.9% of AC, 27.3% of AH and 8.0% of AL were negative, but 93.3% of NNM were positive. It was concluded that the positive staining rate, especially the rate of pattern 3 for each antibody correlated with the degree of atypia of the colorectal neoplastic lesions (AC, AH and AL).

Adenocarcinoma

Regulatory functions for murine intraepithelial lymphocytes in mucosal responses.

Our studies have given direct evidence that CD3+, CD4-, CD8+ T cells in the IELs can be separated into at least two subsets that produce IFN-gamma and/or IL-5 and may exhibit Th1- and Th2-type functions in the epithelium and in the underlying lamina propria region. Further, it was also shown that TCR1+ T cells in IELs are capable of producing IFN-gamma and/or IL-5. In addition to production of these cytokines, IELs derived from mice orally primed with TD antigen contain a subset of T cells which possess antigen-specific immunoregulatory function. CD3+, CD4-, CD8+ T cells isolated from IEL of TD antigen-primed mice abrogated systemic unresponsiveness to secondary-type responses including those of the IgA isotype upon adoptive transfer to mice with OT. Our studies further suggested that these CD3+, CD4-, CD8+ IELs use the gamma-delta form of TCR (TCR1) for their immunoregulatory function.

Animals

Histological classification of nesidioblastosis: efficacy of immunohistochemical study of neuron-specific enolase.

Pancreatic specimens of six patients with nesidioblastosis were studied by light microscopy and immunohistochemistry in order to classify the changes of the endocrine pancreas and relate them to the clinical outcome. Neuron-specific enolase immunostaining was useful in demonstrating the distribution of whole pancreatic endocrine cells. The six cases with nesidioblastosis were classified into two types; four cases of focal type (head 1, body 1, tail 2), and two cases of diffuse type. The histological classification show a correlation to the clinical outcome. The patients with a focal body or tail type showed normal blood sugar levels immediately after operation. On the other hand the patients with both diffuse type and a focal head type needed medical treatment within a few months after operation. Therefore, these cases should be followed with great care postoperatively. A partial 80% to 90% pancreatectomy might be sufficient for each type except for the focal head type. When the intraoperative examination (both macroscopic and microscopic) is suggestive of focal head type, a pancreatectomy of 95% or more is called for.

Cell Count

Copper-induced toxicity in macular mutant mouse: an animal model for Menkes' kinky-hair disease.

These studies were designed to determine if macular mutant mouse, which is a proposed animal model of Menkes' kinky-hair disease, is sensitive to the acute toxic effect of Cu as compared to normal and heterozygote mice. Single sc injection of Cu were administered to 6- to 8-day-old mice, and mortalities were recorded for 30 days. The copper treatment at high doses (12 to 25 mg Cu/kg) was very toxic to mutant mice as compared to normal mice, and almost all mutant mice died within 10 days after injection. The effect of Cu toxicity on heterozygote mice was intermediate. The LD50 values 3 days after injection of Cu were 29.5 mg Cu/kg for normal mice, 23.5 mg Cu/kg for heterozygote mice, and 15.5 mg Cu/kg for mutant mice. In Cu-injected mutant mice (11 and 18 mg Cu/kg), significant elevations in serum aspartate aminotransferase and lactate dehydrogenase activity occurred as compared to Cu-injected normal and heterozygote mice. However, no significant elevations in serum creatinine and urea nitrogen contents in Cu-injected mutant were observed as compared to normal and heterozygote mouse. No significant differences in hepatic metallothionein(MT) and MT-1 mRNA, and serum ceruloplasmin oxidase activity levels were observed between Cu-injected normal and mutant mouse. These results indicated that macular mutant mice was sensitive to the acute toxic or hepatotoxic effects of Cu as compared to normal and heterozygote mice.

Animals