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Biomedical subjects

T Kawaguchi

Publications and source records attributed to T Kawaguchi.

At least 307 records · Page 17Linked to original sources
PubMed1993

3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase.

3-Cyano-2,6-dihydroxypyridine (CNDP) was identified as a potent inhibitor (IC50 value, 4.4 nM) of dihydrouracil dehydrogenase (DHUDase) [EC 1.3.1.2], a rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. The inhibitory activity of CNDP was about 2,000 times that of uracil under our assay conditions. Kinetic analyses with partially purified enzyme from rat liver revealed that the mechanism of inhibition of DHUDase by CNDP was of mixed type with an inhibition constant (Ki) of 1.51 nM. CNDP had less effect on 5-FU phosphorylation than on 5-FU degradation. The inhibitory effect of CNDP on ribosylation of 5-FU was 600 to 1,000 times less than that on DHUDase. Moreover, CNDP did not inhibit uridine kinase, thymidine kinase, or pyrimidine phosphoribosyltransferase. Coadministration of CNDP with 1-ethoxymethyl-5-fluorouracil (EM-FU) to rats with Yoshida sarcoma elevated the level of 5-FU in both the blood and the tumor and enhanced the antitumor effect of EM-FU. These findings indicated that CNDP would be a useful chemical modulator in chemotherapy with 5-FU or its prodrugs.

Alanine↗
PubMed1993

Predictors of disease severity and survival in patients with coronary artery disease.

BACKGROUND: The objective of this study was to determine whether coronary angiographic findings and survival could be predicted using standard clinical and exercise-test data. METHODS: Five hundred and ninety-five men who had undergone both exercise treadmill testing and cardiac catheterization were followed for up to 5 years. Left main (LM) disease (> or = 50% stenosis) was present in 42 patients, whereas 30 patients had LM equivalent disease (> or = 70% stenosis of both the proximal left anterior descending and circumflex coronary artery disease (n = 152), one-vessel disease (n = 186), two-vessel disease (n = 118), three-vessel disease (n = 67), LM or LM equivalent disease without significant (> or = 70%) right coronary artery involvement (n = 26), and LM or LM equivalent disease with right coronary artery involvement (n = 46). RESULTS: ST-segment depression was more marked, whereas ejection fraction, maximal heart rate, maximal systolic blood pressure, and exercise capacity were lower in each group as disease severity worsened. Using Kaplan-Meier analysis, the subgroup with the poorest survival was found to be those with LM or LM equivalent disease with right coronary artery disease, and the next worse was the three-vessel disease group, in which survival was poorer than in all other subgroups (P < 0.01). Stepwise regression analysis revealed that the most powerful predictor for coronary artery disease severity was exercise-induced ST depression (P < 0.001), but it predicted survival poorly. History of congestive heart failure, low ejection fraction (50% or lower), and poor exercise capacity (5 metabolic equivalents or less) emerged as strong predictors of survival using stepwise Cox regression analysis (P < 0.001). CONCLUSION: Exercise-induced ST depression predicted the severity of angiographic disease but not survival, whereas the strongest predictors of survival were history of congestive heart failure, low ejection fraction, and poor exercise capacity.

Adult↗
PubMed1993

Differential effects of acyclothymidine, a potent pyrimidine nucleoside phosphorylase inhibitor, on the pharmacokinetics of doxifluridine in rabbits via oral administration.

Acyclothymidine (AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl)uracil), a potent inhibitor of pyrimidine nucleoside phosphorylase (PyNPase), was co-administered with 5'-deoxy-5-fluorouridine (5'-DFUR), a PyNPase activating prodrug of 5-fluorouracil (5-FU), to rabbits. The absorption and pharmacokinetic parameters of 5'-DFUR and its active metabolite 5-FU, after administration of 5'-DFUR in combination with AcyT, were evaluated in the animals. Animals were given an oral or intravenous administration of 5'-DFUR (50 mg/kg) in combination with an equimolar dose of AcyT (40 mg/kg). The half-lives (t1/2) of 5'-DFUR and 5-FU in plasma were 16.8 and 11.5 min, respectively. AUC (area under the plasma concentration-time curve) of 5'-DFUR and 5-FU following the oral administration of 5'-DFUR (50 mg/kg) was 1710 and 24.3 micrograms.min/ml, respectively. After the oral co-administration of 5'-DFUR and AcyT (at a molar ratio of 1:1), the AUC values for 5'-DFUR and 5-FU increased to 2680 and to 121.1 micrograms.min/ml, respectively. However, this combination had little effect on the t1/2 of 5'-DFUR.

Administration, Oral↗
PubMed1993

Molecular cloning and expression of proteinaceous alpha-amylase inhibitor gene from Streptomyces nitrosporeus in Escherichia coli.

The proteinaceous alpha-amylase inhibitor, T-76, gene was cloned by screening a Streptomyces nitrosporeus genomic library using a deoxyinosine-containing probe corresponding to the amino acid sequence of the inhibitor. The nucleotide sequence of the insert of a positive clone had an open reading frame of 330 bp that encoded a polypeptide of 110 amino acid residues with a calculated molecular mass of 11,306 daltons. The polypeptide begins with proximal basic amino acids and a region rich in hydrophobic amino acids that possibly act as a signal peptide for secretion, which is followed by a sequence consistent with the amino-terminal amino acid sequence of the T-76 inhibitor. Escherichia coli cells harboring the plasmid derivatives for expression produced the inhibitor in their periplasmic space. The amino-terminal sequence of the inhibitor produced by an E. coli transformant was identical to that of the T-76 inhibitor secreted by S. nitrosporeus. The amino acid sequence of the inhibitor deduced from nucleotide sequence showed significant homology to other proteinaceous alpha-amylase inhibitors.

Amino Acid Sequence↗
PubMed1993

Expression of the cellulase (FI-CMCase) gene of Aspergillus aculeatus in Escherichia coli.

FI-CMCase cDNA of Aspergillus aculeatus was expressed in Escherichia coli by using the tac promoter of E. coli. Transformants of E. coli harboring a plasmid pHEM06 containing mature form FI-CMCase cDNA produced FI-CMCase in the cytoplasm of the cells. The enzyme from E. coli cells was purified to yield 56% and it was immunological identical to that of FI-CMCase purified from A. aculeatus.

Amino Acid Sequence↗
PubMed1993

Reduction of leaky lymphocyte clones producing immunoglobulins and thymic lymphocytic leukemia by selective inbreeding of SCID (severe combined immunodeficiency) mice.

Selective inbreeding of C.B17-scid/scid mouse pairs showing undetectable IgG and IgM has been carried out in order to reduce the mortality of mice by early occurrence of thymic lymphocytic leukemia and abnormal lymphocyte clones producing immunoglobulins, both of which inhibit the successful heterotransplantation of normal and neoplastic human tissues. Although the majority of C.B17-scid/scid mice showed undetectable (< 1 microgram/ml) or low level (< or = 25 micrograms/ml) of serum IgG and IgM, some produced abnormally high concentrations of IgG and IgM (> 25 micrograms/ml). The incidence of such mice showing higher levels of IgG was very high at F1 and F2 generation (10/55, 18.2%), but significantly low after the F3 generation (18/446, 4.0%, p << 0.001). Although leukemia incidence was very high at F4 to F5 generations (8/40, 20.0%), death from leukemia was not observed early in life (4-6 months after birth) at F7 to F10 generations (0/36, 0%, p < 0.01) and was very low during the age of 6-10 months after the F8 generation (11/66, 16.7% at F4 and F5 vs 4/93, 4.3% at F8-10), p < 0.01). Scid mice improved by the selective inbreeding will provide an invaluable experimental system for the heterotransplantation of normal and neoplastic human tissues.

Animals↗
PubMed1993

[Gamma delta T cells in the palatine tonsil--immunohistological and functional study].

In the present study, the gamma delta T cell content of the tonsillar T cell population has been evaluated for the first time. Flow cytometric analysis showed that 1.56% of T cells in palatine tonsils obtained from patients with recurrent tonsillitis (n = 17) expressed the gamma delta T cell receptor. Next, the tissue distribution of these cells in palatine tonsil was examined immunohistologically. Gamma delta T cell receptor positive cells and CD3 positive cells were counted in the crypt epithelium, tonsillar epithelium on the free surface and in the interfollicular space (n = 29). The gamma delta T cell content of the whole T cell population in each of these regions was calculated and compared. It was demonstrated that T cells in the crypt epithelium contained more gamma delta T cell receptor bearing cells than did T cells infiltrating the tonsillar epithelium on the free surface. T cells in the interfollicular space included even fewer gamma delta T cells. The gamma delta T cell content of tonsillar T cells showed a gradual decrease with age in each region. Then, infiltration of gamma delta T cells in the crypt epithelium was compared among recurrent tonsillitis, hypertrophic tonsil and focus tonsil (PPP) specimens. Recurrent tonsillitis showed the highest gamma delta T cell content in T cells infiltrating the crypt epithelium. There was no remarkable infiltration of these cells in the crypt epithelium of focus tonsil. Furthermore, the gamma delta T cell population was isolated from tonsillar lymphocytes and stimulated with staphylococcal enterotoxin A (SEA), staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Ultrastructure of invasion of the adult rat hepatocyte monolayer by rat ascites hepatoma variant sublines.

Invasion of a primary cultured adult rat hepatocyte monolayer by rat ascites hepatoma AH7974-derived variant sublines (74AD, 74FL) was studied ultrastructurally. Although 74AD and 74FL are an adherent and a floating subline, respectively, in ordinary in vitro culture, the majority of the cells of both sublines attached to the hepatocytes at the tips of their cytoplasmic processes up to 2 h after coculture. Thereafter, these cells adhered to the hepatocytes with several types of junctional structures. Simple apposition was prominent 6 h after coculture, and intermediate and tight junctions were frequently observed 12 h after coculture. The attached tumor cells separated the intercellular junctions of the hepatocyte monolayer with their cytoplasmic protrusions and became directly adherent to dishes by pushing aside the hepatocytes. In addition, we sometimes found some peculiar interactions which appeared to be an early event of a kind of cytoplasmic fusion between a tumor cell and a hepatocyte after 12 h of coculture. An increasing electron density of mitochondria, the disappearance of cristae, and the presence of cytoplasmic vacuolations were observed in the hepatocytes fused with tumor cells. Such results suggest that the hepatic invasion by tumor cells results from the interaction of tumor cells and hepatocytes leading to their cytoplasmic fusion, as well as to direct migration of tumor cells into hepatic cords. The mechanism of invasion may be independent of that of substrate adhesion.

Animals↗
PubMed1993

[Diagnostic imaging of invasive renal pelvic cancer].

In 5 patients with invasive renal pelvic cancer, we evaluated the imaging features of drip infusion pyelography (DIP), retrograde pyelography (RP), ultrasonography (USG), computerized tomography (CT), magnetic resonance imaging (MRI) and renal angiography (RAG). The different features of high diagnostic value were as follows. DIP revealed no visualization with enlargement and reniform outline. RP revealed irregular, serrated filling defect of the pelvis with destruction of the involved calyces and infundibula. USG revealed loss of normal parenchymal architecture with amputation of the central echo complex due to echogenic mass. CT revealed widened renal parenchyma and the involved parenchymal segment, which was replaced by tumor mass with inhomogeneous density and minimal enhancement. MRI denoted renal vein thrombus. RAG revealed, besides the fine neovascularity with tumor blush, hypovascularity in the involved area. In addition to these features, we believe that in particular, RP, USG, CT and RAG are useful tools for patients with non-functioning kidney.

Angiography↗
PubMed1993

[Efficacy and safety of long-term erythropoietin therapy in chronic hemodialysis patients with renal anemia].

In order to examine the efficacy and safety of long-term erythropoietin (rHuEPO) therapy, 103 hemodialysis patients were treated with rHuEPO for their renal anemia and the effects were observed for 1 year. Within 3 or 4 months after starting the rHuEPO therapy, the hematocrit (Ht) value rose up to nearly 30% and the level was maintained thereafter by approximately 4500 IU per week of rHuEPO. Tachyphylaxis did not occur even after 1 year of rHuEPO treatment. Symptoms such as headache, dizziness or palpitation were markedly reduced with the improvement of anemia. Although blood pressure was modestly elevated (systolic by 9 mmHg, p < 0.01 and diastolic by 5 mmHg, p < 0.01 at 6-month-stage), only 1 patient was forced to stop the therapy. Moreover, the blood pressure was successfully controlled to the original level after 11 months. This blood pressure elevation was not related to the increase of Ht level nor the dose of rHuEPO. Serum protein, lipid, electrolytes and liver enzymes did not change during 1 year of rHuEPO therapy. These results indicate that rHuEPO treatment is effective and innocuous as a long-term therapy of renal anemia in hemodialysis patients.

Anemia↗
PubMed1992

Specific binding sites for 125I-endothelin-1 in the porcine and human spinal cord.

Specific binding sites for 125I-endothelin-1 (125I-ET-1) in the spinal cord were investigated using quantitative receptor autoradiographic and chemical cross-linking methods. The binding sites were highly concentrated in porcine and human spinal cord areas corresponding anatomically to the dorsal horn (Rexed's laminae I-III), an area around the central canal (lamina X) and the principal part of the intermediolateral nucleus (IMLp). The localization of the binding sites differed from those of 125I-omega-conotoxin GVIA (125I-CgTx) and 125I-Bolton-Hunter substance P (125I-BH-SP), with the exception that the IMLp shared 125I-ET-1 with 125I-CgTx and 125I-BH-SP binding sites. Specific 125I-ET-1 binding sites in the areas examined were characteristically single and of high affinity. There were no differences between the potencies of unlabeled ET family peptides, ET-1, ET-2, ET-3 and sarafotoxin S6b at inhibiting 125I-ET-1 binding to the areas. Chemical cross-linking studies showed that 125I-ET-1 and 125I-ET-3 mainly bound to a protein with molecular mass of 43 kDa in the porcine and human thoracic spinal cord membranes. The present finding shows the neuronal significance of this newly discovered peptide in the spinal cord.

Aged↗
PubMed1992

Elevated serum manganese superoxide dismutase in acute leukemias.

We measured the serum levels of manganese-superoxide dismutase (Mn-SOD) in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Serum Mn-SOD level for normal subjects was 94.1 +/- 23.5 ng/ml (mean +/- S.D.), the levels for AML and ALL patients were 159.6 +/- 77.1 ng/ml and 154.4 +/- 77.0 ng/ml, respectively. The serum Mn-SOD levels were unrelated to individual intracellular Mn-SOD levels, but correlated well with serum lactate dehydrogenase values. Regression of the leukemia was accompanied by decrease in the serum level of Mn-SOD. Serum Mn-SOD may thus serve as a measure of the activity of the disease.

Enzyme-Linked Immunosorbent Assay↗
PubMed1992

Antitumor effects of SMANCS on rat mammary tumor induced by 7,12-dimethylbenz[a]anthracene.

We previously found that a high-molecular-weight anticancer agent, polystyrene-co-maleic acid conjugated neocarzinostatin (SMANCS), in which two chains of styrene/maleic acid copolymer are conjugated to the anticancer protein neocarzinostatin (NCS), accumulated more selectively in tumor tissue than in normal tissue and was more stable than NCS in blood. These results indicate that SMANCS should have less systemic toxicity and a better therapeutic effect than NCS. In this study, the antitumor activity and adverse effects of SMANCS were compared with those of NCS by using rat mammary tumor induced by 7,12-dimethylbenz[a]anthracene. When tumors of rats, that had received 7,12-dimethylbenz[a]anthracene (20 mg/kg, one dose, p.o. in oily formulation), became palpable usually after 4-20 weeks, SMANCS treatment was initiated. Thirty days after i.v. administration of SMANCS (0.1 mg/kg 3 times and 0.3 mg/kg 3 times), tumors had shrunk in 35 of 37 rats (a mean weight was about 10% of control value; or decreased to about 30% of the value of before treatment in tumor weight); tumor size had not changed in 1 rat, and in the remaining 1 rat the tumor had enlarged. Thirty days after i.v. administration of NCS, tumors had shrunk in 8 of 14 rats, but the tumor size was unchanged in 1 rat and was enlarged in 5. In the control group, all tumors had enlarged. Development of new tumors was completely prevented by the administration of SMANCS. Histological examination of sequential slices of tumor revealed clear finding of degeneration and tumor encapsulation at 30 days after initial administration of SMANCS, with an accompanying fatty degeneration, but these effects were not observed for tumors treated with NCS. Although red blood cell counts and hemoglobin amounts decreased significantly in rats receiving NCS, no such effects were apparent in the SMANCS group.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Induction of Mn-superoxide dismutase by tumor necrosis factor, interleukin-1 and interleukin-6 in human hepatoma cells.

Effects of Tumor Necrosis Factor (TNF), Interleukin-1 (IL-1), Interleukin-6 (IL-6) and Interferon-gamma (IFN-gamma) on the expression of Mn-superoxide dismutase (Mn-SOD) protein were investigated in human hepatoma cells, Hu-H1, which revealed resistance to the cytotoxicity of TNF and IL-1. Both TNF and IL-1 enhanced the Mn-SOD production to the level of 30- to 40-fold. IL-6 also increased the enzyme protein to 2- to 3-fold of the basal level without any cell proliferative effect. A specific antibody against IL-6 almost completely inhibited the induction of Mn-SOD. IL-6, as well as TNF and IL-1, appears to play some role in the Mn-SOD protein expression in human hepatoma cells.

Antibodies↗