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M Tani

Publications and source records attributed to M Tani.

At least 55 records · Page 3Linked to original sources
PubMed2001

Role of CYP2C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes.

The 4-hydroxylation of mephobarbital enantiomers was investigated by using human liver microsomes from the extensive metabolizers (EM) and poor metabolizers of CYP2C19. The 4-hydroxylase activity of R-mephobarbital in the EM microsomes was >10 times higher than that of S-mephobarbital. In the poor metabolizer microsomes, the 4-hydroxylase activity of R-mephobarbital was much lower than that in the EM microsomes, and the ratio of 4-hydroxylase activity of R-mephobarbital to that of S-mephobarbital was also lower than that in the EM microsomes. Moreover, the 4-hydroxylase activity of R-mephobarbital showed a high correlation (r = 0.985, p<0.001) with the 4'-hydroxylase activity of S-mephenytoin in a panel of nine human liver microsomes. Anti-CYP2C antibody inhibited R-mephobarbital 4-hydroxylase activity by 85% of the control activity. R-Mephobarbital competitively inhibited S-mephenytoin 4'-hydroxylase activity (K(i) = 34 microM), while S-mephenytoin inhibited R-mephobarbital 4-hydroxylase activity (K(i) = 103 microM). Among the seven cDNA-expressed CYPs studied, only CYP2C19 catalyzed R-mephobarbital 4-hydroxylation. These findings suggest that the 4-hydroxylation of mephobarbital catalyzed by CYP2C19 is preferential for R-enantiomer in human liver microsomes.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Primary mediastinal large B-cell lymphoma with sclerosis: a clinical study of 89 patients treated with MACOP-B chemotherapy and radiation therapy.

BACKGROUND AND OBJECTIVES: Primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis has recently been recognized as a specific clinical and pathologic entity for which the best therapeutic approach seems to be a combination of chemotherapy and radiotherapy. DESIGN AND METHODS: Between 1989 and 1998, 89 previously untreated patients with PMLBCL with sclerosis were treated with a combination of a third-generation chemotherapy regimen (MACOP-B) and mediastinal radiation therapy. The response evaluations were examined after chemotherapy and at the end of radiotherapy. RESULTS: Twenty-three (26%) patients achieved a complete response (CR) and 59 (66%) obtained a partial response (PR) after the MACOP-B regimen. After radiation therapy, 55/59 (93%) of the patients in PR achieved CR. The CR rate at the end of the treatment was 88% (78/89). Only 7 (8%) patients were non-responders. Among the 78 patients who obtained a CR there were 7 (9%) relapses in a median follow-up of 5 months (all relapses occurred within 9 months); the other 71 patients are currently in continuous CR with a median follow-upof 45 months (range, 4-110 months). Projected overall survival was 86% at 9 years; the relapse-free survival curve of the 78 patients who achieved CR was 91% at 9 years. INTERPRETATION AND CONCLUSIONS: In patients with PMLBCL with sclerosis, combined modality treatment using the MACOP-B chemotherapy regimen and radiation therapy induces a good remission rate with the patients having a greater than 90% chance of surviving disease-free at 9 years. Radiotherapy often plays a pivotal role in obtaining CR status.

Adolescent↗
PubMed2001

[Prostatic cancer developing after transurethral resection of the prostate for benign prostatic hyperplasia].

From January 1993 to June 1998, 319 cases were histopathologically diagnosed as prostatic cancer. In 7 of the 319 cases (2.2%) transurethral resection of the prostate (TUR-P) had been performed and a diagnosis of benign prostatic hyperplasia had been made with the resected specimens. The interval between TUR-P and the diagnosis of prostatic cancer ranged from 22 months to 15 years. All the cases showed an elevation of the prostate specific antigen (PSA) value (6.4-399 ng/ml, Tandem-R: RIA) at the time of cancer diagnosis. In 2 cases, PSA was measured in cancer screening. The clinical stage was stage B1 in 2 cases, stage B2 in 2 and D2 in 3. Only one case had been regularly followed-up after TUR-P, in which cancer was diagnosed by needle biopsy 22 months after TUR-P, because of the sustained high PSA values. Since most of such patients have an advanced stage of prostate cancer, it is of importance to have periodical follow-up examinations after TUR-P. The measurement of PSA appears the most reliable means in this way.

Aged↗
PubMed2001

Efficacy of vinorelbine, epirubicin and prednisone combination regimen in pretreated elderly patients with aggressive non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: To assess the efficacy and toxic profile of the NAEPP protocol, a regimen including vinorelbine, epirubicin and prednisone, in a particularly troublesome subset of patients: pretreated elderly patients with aggressive non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: From November 1998 to January 2000, 20 pretreated patients who had all relapsed after first-line VNCOP-B chemotherapy were enrolled in a phase II trial and treated with the NAEPP regimen: vinorelbine (25 mg/m(2) i.v. on days 1 and 8), epirubicin (40 mg/m(2) i.v. on days 1 and 8), and prednisone (40 mg/m(2) on days 1 and 8) with granulocyte colony-stimulating factor administered at 5 mg/kg/day on days 2-5 and days 9-12. Chemotherapy was repeated every 4 weeks for a total of 6 cycles. RESULTS: Six (30%) patients achieved complete remission (CR) and 7 (35%) had partial responses (PR), giving an overall response rate of 65%. The response rate was not affected either by type of relapse presentation (nodal versus nodal plus extranodal), presence of bulky disease, or time of relapse. No major toxic effects were recorded. INTERPRETATION AND CONCLUSIONS: These preliminary data suggest that the NAEPP regimen is an effective combination with a low toxicity profile in elderly pretreated patients with aggressive NHL. Further trials using NAEPP as a consolidation phase following first-line treatment are needed to establish the advantage in terms of CR rate and relapse-free survival in these patients.

Aged↗
PubMed2001

[Combination effect of arbekacin and cefepime on mixed culture of MRSA and P. aeruginosa].

We investigated the in vitro combination effects of arbekacin (ABK), vancomycin (VCM) or teicoplanin (TEIC) and cefepime (CFPM) on methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa isolated from various clinical specimens. Using checkerboard titration technique by agar dilution, combinations of ABK, VCM or TEIC and CFPM exhibited synergistic effects on 25 MRSA strains. The similar effects were also observed on ABK-resistant MRSA. Combination of ABK and CFPM exhibited a good effect on P. aeruginosa, but combinations of VCM or TEIC and CFPM exhibited no synergistic effect on P. aeruginosa. In vitro bactericidal activities of ABK, VCM or TEIC and CFPM against mixed cultures of MRSA with P. aeruginosa were examined at concentration of each drug that corresponds to the serum concentration at 3 hours after the usual therapeutic dosage. VCM or TEIC alone showed bacteriostatic effects against MRSA, and no enhancements were observed when combined with CFPM. ABK alone showed good bactericidal activity against MRSA and combination with CFPM enhanced the bactericidal activity. Against P. aeruginosa, ABK or CFPM alone showed the bactericidal activity, and strong bactericidal activity was induced by the combination of ABK and CFPM. VCM and TEIC showed no bactericidal activities against P. aeruginosa. When CFPM combined with VCM or TEIC, the bactericidal activity of CFPM was not enhanced against P. aeruginosa.

Aminoglycosides↗
PubMed2001

Pharmacokinetic study of human natural beta-interferon in patients with end-stage renal failure.

AIMS: Although human natural beta-interferon (beta-IFN) is currently used in the treatment of a number diseases, there have been no published studies of the pharmacokinetics and pharmacodynamics of beta-IFN in patients with end-stage renal failure. MATERIALS: Five maintenance hemodialysis patients with chronic hepatitis C (4 men and 1 woman) were enrolled in this study. METHODS: For the pharmacokinetic study, blood samples were obtained from a forearm vein at intervals, before infusion and 0, 3, 5, 10, 20, 30, and 40 minutes after a 15-minute intravenous infusion of human natural beta-IFN (Feron, Toray Industries, Inc., Tokyo) at a dose of 600 MIU. RESULTS: Intravenous beta-IFN was administrated safely to all five patients. The plasma half-life of beta-IFN was found to be 6.91 +/- 2.80 (mean +/- SD) minutes. The initial volume of distribution was found to be 0.49 +/- 0.02 l/kg. CONCLUSION: A 15-minute intravenous infusion of human natural beta-IFN was safely administered to the hemodialysis patients. This pharmacokinetic study showed that it is not necessary to reduce the dosage in patients with end-stage renal failure.

Alanine Transaminase↗
PubMed2000

Neutral/alkaline and acid ceramidase activities are actively released by murine endothelial cells.

Ceramidases (CDase(s)) play a key role in sphingolipid metabolism by hydrolyzing ceramide into sphingosine. Here we report that murine endothelial cells, macrophages, and human fibroblasts are all able to release acid as well as neutral/alkaline CDase activities in the culture medium. Endothelial cells were characterized by the highest specific activity of cellular as well as secreted CDases. The release of both enzymatic activities was reduced by protein synthesis inhibitor cycloheximide but was unaffected by the blocking of RNA transcription with actinomycin D. The discharge of acid and neutral/alkaline CDases was also diminished by brefeldin A, a fungal metabolite which disrupts Golgi apparatus. Remarkably, treatment of endothelial cells with bradykinin resulted in a significant increase of neutral/alkaline but not acid CDase release. This report represents the first evidence for the existence of constitutive and regulated release of CDase activities by endothelial cells. In view of the known ability of these cells to secrete sphingomyelinase, this finding suggests that CDase may participate in extracellular sphingomyelin metabolism which is presently known to have a role in atherogenesis and could be involved in other physiological or pathological events.

Acid Ceramidase↗
PubMed2000

gamma-catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta-catenin.

beta-Catenin and gamma-catenin (plakoglobin), vertebrate homologs of Drosophila armadillo, function in cell adhesion and the Wnt signaling pathway. In colon and other cancers, mutations in the APC tumor suppressor protein or beta-catenin's amino terminus stabilize beta-catenin, enhancing its ability to activate transcription of Tcf/Lef target genes. Though beta- and gamma-catenin have analogous structures and functions and like binding to APC, evidence that gamma-catenin has an important role in cancer has been lacking. We report here that APC regulates both beta- and gamma-catenin and gamma-catenin functions as an oncogene. In contrast to beta-catenin, for which only amino-terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of gamma-catenin had similar transforming activity. gamma-Catenin's transforming activity, like beta-catenin's, was dependent on Tcf/Lef function. However, in contrast to beta-catenin, gamma-catenin strongly activated c-Myc expression and c-Myc function was crucial for gamma-catenin transformation. Our findings suggest APC mutations alter regulation of both beta- and gamma-catenin, perhaps explaining why the frequency of APC mutations in colon cancer far exceeds that of beta-catenin mutations. Elevated c-Myc expression in cancers with APC defects may be due to altered regulation of both beta- and gamma-catenin. Furthermore, the data imply beta- and gamma-catenin may have distinct roles in Wnt signaling and cancer via differential effects on downstream target genes.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Molecular cloning of a novel NF2/ERM/4.1 superfamily gene, ehm2, that is expressed in high-metastatic K1735 murine melanoma cells.

We have cloned a novel gene, Ehm2, that is expressed in high-metastatic but not in low-metastatic K-1735 murine melanoma cells. The Ehm2 gene encodes a protein of 527 amino acid residues, showing up to 41% amino acid identity with the FERM domain of NF2/ERM/4.1 superfamily proteins, which have the function of connecting cell surface transmembrane proteins to cytoskeletal molecules. The Ehm2 gene was mapped to chromosome 4 and was expressed in the liver, lung, kidney, and testis and in 7- to 17-day embryos. The highest level of homology was observed with NBL4, which is a new subfamily protein of the NF2/ERM/4.1 superfamily. A human homologue of the mouse Ehm2 gene, showing significant homology (83% identity), was identified in the genomic DNA and EST databases. Furthermore, seven rat EST clones and one pig EST clone in the GenBank EST database were identified as having 83-92% sequence homology with the cDNA sequence of the mouse Ehm2 gene. Thus, Ehm2 is a highly conserved gene that encodes a novel member of the NF2/ERM/4.1 superfamily proteins.

Animals↗
PubMed2000

Molecular cloning of the full-length cDNA encoding mouse neutral ceramidase. A novel but highly conserved gene family of neutral/alkaline ceramidases.

We report here the molecular cloning, sequencing, and expression of the gene encoding the mouse neutral ceramidase, which has been proposed to function in sphingolipid signaling. A full-length cDNA encoding the neutral ceramidase was cloned from a cDNA library of mouse liver using the partial amino acid sequences of the purified mouse liver ceramidase. The open reading frame of 2,268 nucleotides encoded a polypeptide of 756 amino acids having nine putative N-glycosylation sites. Northern blot analysis revealed that the mRNA of the ceramidase was expressed widely in mouse tissues, with especially strong signals found in the liver and kidney. The ceramidase activity of lysates of CHOP cells increased more than 900-fold when the cells were transformed with a plasmid containing the cDNA encoding ceramidase. We also cloned the ceramidase homologue from the cDNA library of mouse brain and found that the sequence of the open reading frame, but not the 5'-noncoding region, was identical to that of the liver. Interestingly, phylogenetic analysis of various ceramidases clearly indicated that neutral/alkaline ceramidases form a novel but highly conserved gene family that is evolutionarily different from lysosomal acid ceramidases.

Amidohydrolases↗
PubMed2000

Purification and characterization of a neutral ceramidase from mouse liver. A single protein catalyzes the reversible reaction in which ceramide is both hydrolyzed and synthesized.

We report here a novel ceramidase that was purified more than 150, 000-fold from the membrane fraction of mouse liver. The enzyme was a monomeric polypeptide having a molecular mass of 94 kDa and was highly glycosylated with N-glycans. The amino acid sequence of a fragment obtained from the purified enzyme was homologous to those deduced from the genes encoding an alkaline ceramidase of Pseudomonas aeruginosa and a hypotheical protein of the slime mold Dictyostelium discoideum. However, no significant sequence similarities were found in other known functional proteins including acid ceramidases of humans and mice. The enzyme hydrolyzed various N-acylsphingosines but not galactosylceramide, sulfatide, GM1a, or sphingomyelin. The enzyme exhibited the highest activity around pH 7.5 and was thus identified as a type of neutral ceramidase. The apparent K(m) and V(max) values for C12-4-nitrobenzo-2-oxa-1, 3-diazole-ceramide and C16-(14)C-ceramide were 22.3 microM and 29.1 micromol/min/mg and 72.4 microM and 3.6 micromol/min/mg, respectively. This study also clearly demonstrated that the purified 94-kDa ceramidase catalyzed the condensation of fatty acid to sphingosine to generate ceramide, but did not catalyze acyl-CoA-dependent acyl-transfer reaction.

Alkaline Ceramidase↗
PubMed2000

In vitro augmentation of antitumor effect in combination with CPT-11 and CDDP for human colorectal cancer.

BACKGROUND AND OBJECTIVES: Irinotecan hydrochloride (CPT-11) is one of the camptothecin analogues that has shown a broad spectrum of strong antitumor effectiveness against various cancers, including colorectal cancer. In order to promote the clinical response of chemotherapy for colorectal cancer using CPT-11, one of the most effective strategies is to use it in combination with other anticancer agents. In the present study, anticancer effects after combining CPT-11 and other antitumor agents were determined by a 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay of colorectal cancer cells, especially freshly isolated cancer cells. METHODS: Freshly isolated cancer cells from 20 patients with colorectal cancer and the established colon cancer cell lines were used in this study. The augmentation of the antitumor effectiveness of 7-ethyl-10-hydroxy-CPT (SN-38) was analyzed in combination with other anticancer agents. Furthermore, the antitumor effectiveness using lower concentrations of anticancer agents was measured to understand the mechanism of the augmentation. RESULTS: The percent inhibition of SN-38 in combination with cisplatin (CDDP) and mitomycin revealed a high anticancer effect compared with each anticancer agent alone for freshly isolated rectal cancer. CDDP also had a synergistic effect in combination with SN-38 according to the fractional product concept. At lower than plasma peak concentrations of SN-38, the anticancer effects were augmented in combination with lower concentrations of CDDP for freshly isolated colorectal cancer. This augmentation showed a strong synergistic effect. CONCLUSIONS: These results may be supportive to ongoing clinical studies of chemotherapy by using CPT-11 and CDDP for advanced colorectal cancer.

Adenocarcinoma↗
PubMed2000

Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes.

Studies to identify the cytochrome P450 (CYP) isoform(s) involved in chlorpromazine 7-hydroxylation were performed using human liver microsomes and cDNA-expressed human CYPs. The kinetics of chlorpromazine 7-hydroxylation in human liver microsomes showed a simple Michaelis-Menten behavior. The apparent Km and Vmax values were 3.4+/-1.0 microM and 200.5+/-83.7 pmol/min/mg, respectively. The chlorpromazine 7-hydroxylase activity in human liver microsomes showed good correlations with desipramine 2-hydroxylase activity (r = 0.763, p < 0.05), a marker activity for CYP2D6, and phenacetin O-deethylase activity (r = 0.638, p < 0.05), a marker activity for CYP1A2. Quinidine (an inhibitor of CYP2D6) completely inhibited while alpha-naphthoflavone (an inhibitor of CYP1A2) marginally inhibited the chlorpromazine 7-hydroxylase activity in a human liver microsomal sample showing high CYP2D6 activity. On the other hand, alpha-naphthoflavone inhibited the chlorpromazine 7-hydroxylase activity to 55-65% of control in a human liver microsomal sample showing low CYP2D6 activity. Among eleven cDNA-expressed CYPs studied, CYP2D6 and CYP1A2 exhibited significant activity for the chlorpromazine 7-hydroxylation. The Km values for the chlorpromazine 7-hydroxylation of both cDNA-expressed CYP2D6 and CYP1A2 were in agreement with the Km values of human liver microsomes. These results suggest that chlorpromazine 7-hydroxylation is catalyzed mainly by CYP2D6 and partially by CYP1A2.

Antipsychotic Agents↗
PubMed2000

Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation.

This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS) and post-traumatic inflammation. We provide evidence that chemokines play a role in amplifying the inflammatory reaction in EAE (and, probably, MS). In the context of neural trauma, chemokines appear to be primary stimuli for leukocyte recruitment. Strikingly, expression of monocyte chemoattractant protein (MCP)-1 and interferon-gamma-inducible protein-10 (IP-10) are largely restricted to astrocytes or other glial cells in these diverse pathological states. The remainder of the review focuses on studies that address the molecular mechanisms which underlie transcriptional regulation of three astrocyte-derived chemokines: MCP-1, IP-10 and beta-R1/interferon-gamma-inducible T-cell chemoattractant (I-TAC). Based on these studies, we propose that the complex promoters of these genes are marvelously organized for flexible and efficient response to challenge. In the case of MCP-1, several different stimuli can elicit gene transcription, acting through a conserved mechanism that includes binding of inducible transcription factors and recruitment of the constitutive factor Sp1. For IP-10 and beta-R1/I-TAC, it appears that efficient gene transcription occurs only in highly inflammatory circumstances that produce aggregates of simultaneous stimuli. These characteristics, in turn, mirror the expression patterns of the endogenous genes: MCP-1 is expressed under a variety of circumstances, while IP-10 appears primarily during immune-mediated processes that feature exposure of resident neuroglia to high levels of inflammatory cytokines.

Autoimmune Diseases of the Nervous System↗
PubMed2000

Mitogen-activated protein kinase, ERK1/2, is essential for the induction of vascular endothelial growth factor by ionizing radiation mediated by activator protein-1 in human glioblastoma cells.

Vascular Endothelial Growth Factor (VEGF)/Vascular Permeability Factor plays an important role in angiogenesis and cell proliferation of cancer cells. Glioblastoma cells are most malignant and show resistance to radiation therapy inducing VEGF to cause angiogenesis and brain edema. In the present study, the regulatory mechanism of the expression of VEGF by ionizing radiation was studied in three human glioblastoma cells. Induction of VEGF mRNA by ionizing radiation was dependent on dose and incubation time. Activator protein-1 (AP-1) was activated by 10 Gy of ionizing radiation in 1 h in T98G glioblastoma cells on an electrophoretic mobility shift assay. We constructed chimeric genes containing various regions of the VEGF promoter gene and the coding region for chloramphenicol acetyltransferase (CAT) and transiently transfected them to T98G cells. CAT assay with the VEGF promoter gene containing an AP-1 site demonstrated that the promoter activity of the VEGF gene was enhanced by ionizing radiation. Immunological analysis of the activity of mitogen-activated protein kinase, ERK1/2, showed that this activity is up-regulated by ionizing radiation. These results suggest that ERK1/2 pathway is involved in the up-regulation of VEGF expression ionizing radiation mediated by AP-1, which may lead to further neovascularization and proliferation of glioblastoma cells resistant to radiation therapy.

Blotting, Northern↗
PubMed2000

Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage.

The role of focal brain damage as a trigger for autoimmune inflammation in multiple sclerosis (MS) is unclear. In this study we examine mechanisms by which experimental autoimmune encephalomyelitis (EAE) is enhanced by focal brain damage. EAE was produced in Lewis rats by footpad inoculation; focal brain damage, in the form of a cortical cryolesion (cryolesion-EAE), was induced 8 days post-inoculation (d.p.i.). The distribution of inflammation and chemokine production in cryolesion-EAE and EAE-only were compared. Inflammation in the brain, measured by immunocytochemistry for T lymphocytes (W3/13) and microglial activation (MHC class II -OX6), was significantly enhanced in cryolesion-EAE 11-15 d.p.i. (p < 0.01-0.05) but by 20-40 d.p.i., equated with EAE-only. Inflammation in cryolesion-EAE related to breakdown of the blood-brain barrier (BBB) at the site of the cryolesion and also to the corticospinal tracts and thalamus, reflecting the afferent and efferent neuronal connections with the cryolesioned cortex. Semiquantitative RT/PCR dot-blot hybridization assay showed a 6-fold increase in mRNA for specific chemokines in the brain in cryolesion-EAE at 9 d.p.i. (MCP-1) and 11 d.p.i. (MCP-1 and MCP-5) with no significant increase in RANTES, GRO-alpha, or MIP-1alpha. By 14 d.p.i., the levels of MCP-1 and MCP-5 mRNA equated with EAE-only animals. These results suggest that enhancement and location of autoimmune inflammation in the brain following focal cortical injury initially involve chemokines such as the macrophage chemoattractants MCP-1 and MCP-5, and the activities of afferent and efferent neuronal connections with the site of damage. By analogy, similar factors may modulate or reactivate autoimmune inflammation in MS.

Animals↗