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Biomedical subjects

K Gomi

Publications and source records attributed to K Gomi.

At least 73 records · Page 4Linked to original sources
PubMed1997

G1 accumulation caused by iron deprivation with deferoxamine does not accompany change of pRB status in ML-1 cells.

We analyzed G1 accumulation induced by the iron chelator deferoxamine B mesylate (DFO) compared it with that caused by etoposide and cytosine arabinoside (AraC). The results showed that p53 protein increased with all three treatments without an increase in p53 mRNA. After treatment for 3 or 6 h, p21 mRNA increased with 10(-4) DFO to 159% or 556% of pretreatment levels, to 509% or 391% with 10(-5) etoposide, and to 263% or 304% with 10(-5) AraC. Induction of p21 protein was not observed with fluorescence activated cell sorting and Western blot analysis after treatment with DFO or AraC. Treatment with DFO did not cause any change in levels of CDK4 mRNA or protein, whereas etoposide or AraC treatment did diminish CDK4 protein. Enzyme linked immunosorbent assay for pRB and its phosphorylation, which reflects CDK4 activity, revealed that treatment with DFO did not change the amount of pRB or the phosphorylation status. Results of this investigation show that the mechanism of G1 accumulation induced by DFO involves a p53-independent pathway and that expression of p21 protein may be regulated posttranscriptionally.

Cell Division↗
PubMed1997

Design and synthesis of potent antitumor 5,4'-diaminoflavone derivatives based on metabolic considerations.

Recently, we reported that 5,4'-diaminoflavone (1) exhibits potent and specific growth-inhibitory activity against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7. However, when compound 1 was incubated with S-9 mix, its metabolites were observed. Moreover, addition of S-9 mix to the medium caused the drastic decrease in activity of compound 1. Since the 6-, 8-, and 3'-positions were considered to be metabolized oxidatively in vivo from MO calculations, a series of 5,4'-diaminoflavone derivatives substituted at such putative metabolic positions with various functional groups were synthesized aiming at the metabolically stable derivatives. Among them, 5,4'-diamino-6,8,3'-trifluoroflavone (14d) exhibited strong growth-inhibitory activity against MCF-7 cells even in the presence of S-9 mix. Moreover, orally administered compound 14d completely suppressed the growth of MCF-7 inoculated into nude mice, and the effect was more potent than that of compound 1. In addition to ER-positive breast cancer cells, compound 14d exhibited growth-inhibitory activity against a panel of human cancer cell lines including a part of ER-negative breast, endometrial, ovarian, and liver cancers. From these results, fluorine introduction to the putative metabolic positions of compound 1 was elucidated to be effective in the enhancement of the in vivo antitumor activity, probably due to the block of the metabolic deactivation.

Animals↗
PubMed1997

Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing cinnamoyl groups.

A series of N-cinnamates of the A-ring pyrrole compound of duocarmycin were synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. The 4'-methoxy- and 4'-BocNH-cinnamates exhibited strong in vitro anticellular activity among the synthesized compounds. The ortho substitution of the 4'-methoxycinnamate did not affect the anticellular activity and contributed to an enhancement of water solubility. Most of the 8-O-(N,N-dialkylcarbamoyl) derivatives of the 4'-methoxycinnamate displayed remarkably superior in vivo antitumor activity to duocarmycin A or B2. Moreover, it is noteworthy that these 8-O-(N,N-dialkylcarbamoyl) derivatives exhibited significant antitumor activity at wider range of doses as compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment B.

Animals↗
PubMed1997

Treatment for non-Hodgkin's lymphoma (stage I, II) of the elderly: usefulness of local and regional irradiation and reduced dose chemotherapy.

PURPOSE: To examine the usefulness and safety of a new treatment regimen consisting of irradiation to the involved area and adjacent lymph node area, and reduced dose chemotherapy for elderly patients with non-Hodgkin's lymphoma. METHODS AND MATERIALS: The core of this study was 38 elderly patients older than 65 years old with intermediate or high grade non-Hodgkin's lymphoma, and concomitantly suffering from some other geriatric disease. They received involved area irradiation (40 Gy), adjacent lymph node irradiation (30 Gy), and reduced dose chemotherapy (two cycles of 50-70% ACOP: Doxorubicin, Cyclosphosphamide, Vincristine, Prednisone or 70% MACOP-B: Doxorubicin, Cyclophosphamide, Vincristine, Methotrexate, Bleomycin, Prednisone for 4 weeks). RESULTS: The completion rate of the treatment regimen was 100%. The 5-year local control rate was 98%. The 5-year disease-free survival rate and the 5-year cause-specific survival rate for all patients were 70 and 82%, respectively. No treatment deaths were observed, and the rate of serious complications arising from the treatment was 3%. CONCLUSIONS: The newly conducted treatment regimen proved to be safe and useful for elderly patients with non-Hodgkin's lymphoma concomitantly suffering from some other geriatric disease.

Aged↗
PubMed1997

Reversibility of monocytic differentiation of HL-60 cells by 1alpha,25 dihydroxyvitamin D3.

Although 1alpha,25(OH)2D3 induces HL-60 cells to differentiate into monocytes, whether or not these monocytes revert to native promyelocytes is not clear. To investigate this question, HL-60 cells were treated with 1alpha,25(OH)2D3, and divided into CD14-positive and -negative cells with a cell sorter. These two populations were cultured with or without 1alpha,25(OH)2D3. Sorted CD14-positive HL-60 cells, treated with 1alpha,25(OH)2D3 for 7 days, reverted to CD14-negative cells and promyelocyte-like cells if 1alpha,25(OH)2D3 was removed from the medium. We conclude that the 1alpha,25(OH)2D3-induced differentiation of HL-60 cells into monocytes is reversible, and continuous administration of 1alpha,25(OH)2D3 is required for the differentiation of HL-60 cells.

Calcitriol↗
PubMed1997

Effect on an iron-chelator on ascorbate-induced cytotoxicity.

We investigated the effect of deferoxamine mesylate (DFO), an iron chelator, to test whether ascorbate-induced cytotoxicity is due to iron-catalyzed oxidation. Exposing human promyelocytic leukemic HL-60 cells to either sodium ascorbate or ascorbic acid for 1 h resulted in the progressive production of apoptotic cells characterized by cell shrinkage, as well as nuclear and internucleosomal DNA fragmentation. The addition of micromolar to millimolar concentrations of DFO during the 1-h exposure did not inhibit, but rather enhanced the ascorbate-induced apoptosis in both regular and serum-free RPMI1640 medium. However, a higher concentration of serum significantly inhibited the ascorbate-induced cytotoxicity. In contrast, the cytotoxic activity of ascorbate against T98G human glioblastoma cells was enhanced or reduced by micromolar and millimolar concentrations of DFO, respectively. Ascorbate significantly increased the oxidation potential in the culture medium, and the pro-oxidant action of ascorbate was further augmented by the presence of the cells. DFO did not significantly affect the ascorbyl radical intensity and only slightly reduced the ascorbate-elevated oxidation potential. These data demonstrated that ascorbate can induce cytotoxicity even in iron-deficient medium.

Apoptosis↗
PubMed1997

Studies on duocarmycin SA and its derivatives.

New duocarmycin SA derivatives have been synthesized and evaluated for in vitro anticellular activity against HeLa S3 cells, and in vivo antitumor activity against murine sarcoma 180 in mice. The results suggested that the N,N-dialkylcarbamoyl derivatives bearing the p-methoxy cinnamoyl group, which was prepared from duocarmycin SA, showed good in vivo antitumor activities superior to native duocarmycin SA.

Animals↗
PubMed1997

Blood pressure, insulin, and haematocrit values in Japanese subjects over 60 years of age.

Many studies have suggested an association between blood pressure (BP) and both insulinaemia and haematocrit values in Western populations. However, relatively few data regarding such associations for the Japanese population are available. We investigated the relationship between BP and various parameters, including insulin and haematocrit, in 269 healthy Japanese individuals (113 men and 156 women) over 60 years of age. The data were analysed by stepwise multiple regression analysis. In men, the most important determinant of systolic BP (SBP) and diastolic BP (DBP) was the plasma insulin concentration (beta = 0.32, F = 12.4, P < 0.001 and beta = 0.32, F = 13, P < 0.001, respectively), and haematocrit was found to be associated with DBP (beta = 0.21, F = 5.3, P < 0.05). In women, fasting insulins were unrelated to BP, but fasting plasma glucose and triglyceride concentrations and age were associated with SBP (beta = 0.29, F = 15.5, P < 0.001, beta = 0.27, F = 14.3, P < 0.001, and beta = 0.2, F = 7.8, P < 0.01, respectively), and haematocrit, fasting plasma glucose concentration and age were associated with DBP (beta = 0.29, F = 14, P < 0.001, beta = 0.2, F = 6.9, P < 0.01 and beta = 0.2, F = 6.3, P < 0.05, respectively). These results suggest that the insulin-BP associations in healthy Japanese subjects over 60 years of age differ according to sex, and that haematocrit is an important determinant of DBP in both sexes in our population.

Aged↗
PubMed1997

CTLA4 gene polymorphism confers susceptibility to Graves' disease in Japanese.

Susceptibility to Graves' disease (GD) is determined by environmental and genetic factors. The genetic susceptibility to GD is conferred by genes in the human leukocyte antigen (HLA), and several other genes unlinked to HLA are thought to contribute to the development of GD. Three recent papers described the association of GD with the CTLA-4 gene. CTLA-4 is a candidate gene for T-cell mediated autoimmune diseases because it is a negative regulator of T-cell proliferation. As CTLA-4 association with GD may be influenced by the racial composition of the population, it is important to study it in other ethnic groups. We investigated the distribution of CTLA-4 gene polymorphism in 153 Japanese patients with GD (35 males and 118 females) and 200 controls (96 males and 104 females). An A/G transition at position 49 of exon 1 was analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The distribution of genotype frequencies differs between GD and controls (chi2 = 9.46, 2 degrees of freedom, p < 0.01). The presence of at least one G allele (GG or AG) conferred an odds ratio of 2.64 (95% CI = 1.92-3.36). The present study supported the association of the CTLA-4 gene with GD in Japanese and showed that the CTLA4 gene could be one of the non-HLA linked susceptibility genes for GD.

Abatacept↗
PubMed1997

The antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) on tissue factor-induced disseminated intravascular coagulation in crab-eating monkeys (Macaca fascicularis).

We evaluated the antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) in plasma and in a monkey model. rhsTM dose-dependently prolonged activated partial thromboplastin time (APTT) in the following order: humans > monkeys > rats >> rabbits. The prolongation of APTT by rhsTM was also observed in protein C-deficient plasma. rhsTM activated protein C and inactivated factor Va in human and monkey plasma, but not in rat plasma. These findings suggest that the antithrombotic activities of rhsTM are fully expressed in human and monkey. Therefore, to evaluate the whole activity of rhsTM in a clinical model, tissue factor (TF) was intravenously infused into crab-eating monkeys to induce disseminated intravascular coagulation (DIC). Pretreatment with rhsTM reduced fall in fibrinogen with a biphasic and moderate dose-dependency curve, and reduced thrombin-antithrombin III (TAT) levels with a flat linear dose-dependency, while heparin prevented fall in fibrinogen with a steep linear dose-dependency curve without reducing TAT levels. Further evidence suggesting that rhsTM activates protein C in vivo was also obtained. Taken together, the data indicate that rhsTM fully expresses its antithrombotic activities in human and monkey but not in rat and rabbit, and rhsTM prevents TF-induced DIC in monkeys by suppressing thrombin generation.

Animals↗
PubMed1997

Clinical stage IE primary lymphoma of the nasal cavity: radiation therapy and chemotherapy.

PURPOSE: To determine the appropriate radiation therapy and chemotherapy for primary lymphoma of the nasal cavity to improve the local control and survival rates. MATERIALS AND METHODS: Of the 25 adult patients with stage IE nasal lymphoma, nine underwent local radiation therapy alone and 16 underwent radiation therapy and chemotherapy (intravenous infusion). Radiation doses to the involved area were 22-54 Gy (median dose, 49 Gy). RESULTS: The 5- and 10-year cause-specific survival rates were 91% and 73%, respectively. The 5- and 10-year disease-free survival rates were 83% and 59%, respectively. Eight patients developed recurrent disease: six at the local site, one in the cervical nodes, and one in the small intestine. Five of the six patients with local recurrence received less than 50 Gy. Four of the six patients developed recurrent disease in the treated area; the other two patients developed marginal recurrences. Prognostic factors such as age, sex, maximum tumor size, and lactate dehydrogenase level were of limited value. CONCLUSION: The most common recurrence site was the local site. To improve the local control rate, the involved area should be treated with high-dose radiation therapy. The clinical results did not demonstrate the usefulness of combination chemotherapy for stage IE nasal lymphoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Presence of Epstein-Barr virus genome in the bone marrow of patients with hematopoietic malignancies.

The Epstein-Barr virus (EBV) genome was detected by polymerase chain reaction (PCR) in mononuclear cells from bone marrows with diverse types of hematopoietic malignancies. Viral repeated sequences (BamHI-W region) were detected in 42 of 82 (51%) hematopoietic malignancies, including polycythemia vera, but not in nonneoplastic cases. EBV-positive cases were found to consist of various histological types. We did not detect any EBV PCR product in the peripheral blood. The EBV BamHI-Y, -H region, encoding EBV nuclear antigen 2 DNA, which is a single-copy gene in the viral genome, was detected in only 13 of 42 BamHI-W-positive cases, suggesting that the copy number of the EBV genome differed in each case. In all cases, the PCR band was verified by Southern blot hybridization using specific EBV probes. Whether the infected virus is an etiologic agent of the malignancy or merely a latent infection cannot be determined by the PCR assay performed under these conditions. These results, however, suggest that a novel form of EBV latent infection is present in the bone marrow of patients with hematopoietic malignancies.

Adult↗
PubMed1997

Abnormalities in the protein C anticoagulant pathway detected by a novel assay using human thrombomodulin.

We developed a novel assay using human thrombomodulin (TM), which detected overall abnormalities in the protein C anticoagulant pathway (PC pathway). This assay indicates the degree of inhibition of prothrombinase by TM, which is represented as the percentage of prothrombinase inhibition by 25 ng/ml of TM, termed PIP25 (Prothrombinase Inhibition Percentage). We examined PIP25 in plasma samples from patients with systemic lupus erythematosus (SLE) with or without lupus anticoagulant (LA), patients with Behcet's disease (BD), and patients with miscellaneous thrombotic vasculitis and compared these with the PIP25 of plasma samples from healthy volunteers in Japan. The PIP25S were significantly lower in SLE alone (35.5 +/- 12.8%, P = 0.036) and SLE with LA (33.0 +/- 13.3%, P = 0.030) and BD (33.3 +/- 13.4%, P = 0.010) than those in healthy volunteers (43.5 +/- 10.7%). There was no significance between healthy PIP25 and those with miscellaneous thrombotic vasculitis (44.2 +/- 8.4%, P = 0.823). These results suggest that the abnormalities of the protein C anticoagulant pathway were present in patients with SLE(LA) and BD.

Behcet Syndrome↗
PubMed1997

[Analysis of genome-type, serovar and antibiotic susceptibility of Pseudomonas aeruginosa isolated in Beijing Hospital China in 1991 to 1993].

We analyzed the in vitro antibiotic susceptibility pattern and serovar for 192 strains of Pseudomonas aeruginosa isolated at Beijing Hospital(China) from October 1991 to October 1993. The frequency of resistant strains was high, more than 15%, for ceftazidime, cefsulodin, cefoperazone, aztreonam, gentamicin, tobramycin, tosufloxacin, ofloxacin and fosfomycin. The incidence of resistants against piperacillin and imipenem was significantly low. Among the 192 strains, 16 were designated as being multi-drug resistant strains(i.e.; resistant to more than 8 drugs out of 11 drugs), and all of the multi-drug resistant strains were isolated from inpatients. Predominant serovar of 192 strains were 60(31.3%) for G, 28(14.7%) for E, and 24(12.5%) for I. Multi-drug resistant strains have no characteristic serovar. Restriction enzyme SpeI digestion analysis(using pulse field electrophoresis) of P. aeruginosa-genome yielded several common patterns, and was shown to be useful for tracing the route of nosocomial infection. Further, isolates with closely related genome type, in which the size of one digested band was different, showed a different minimum inhibitory concentration of fosfomycin in one genome type or new quinolones in the other genome type. Analysis of genome type and antibiotic susceptibility pattern may exhibit the antibiotic resistant gene.

Anti-Bacterial Agents↗
PubMed1996

Cloning of the polyketide synthase gene atX from Aspergillus terreus and its identification as the 6-methylsalicylic acid synthase gene by heterologous expression.

Southern blot analysis of genomic DNAs of several fungi that produce polyketide compounds with the 6-methylsalicylic acid synthase (MSAS) gene of Penicillium patulum as a probe indicated the presence of an MSAS-homologous gene in the (+)-geodin-producing strain IMI 16,043 of Aspergillus terreus. The gene, designated atX was cloned from an A. terreus genomic DNA library and 7588 bp of the gene together with its flanking regions were sequenced to reveal the presence of a 5.5 kb open reading frame coding for a protein of 1800 amino acids with 190 kDa molecular mass. The presence of a short (70 bp) intron near the N-terminus of the atX gene was predicted that contains the canonical GT and AG dinucleotides at its 5'- and 3'-splicing junctions. The predicted ATX polypeptide showed high homology with P. patulum MSAS along the whole sequence. On the other hand, slight homology was detected only around the beta-ketoacyl synthase regions of Aspergillus nidulans wA, PKSST and Colletotrichum lagenarium PKS1. No transcription of atX was observed throughout the culture period by Northern blotting analysis. To identify the function of the polypeptide encoded by the atX gene, its coding region was introduced into the fungal expression vector pTAex3 under the control of the amyB promoter. The constructed expression plasmid was introduced into A. nidulans. The transformant produced significant amounts of 6-methylsalicylic acid, the structure of which was identified by physicochemical analysis. This result unambiguously demonstrated that the atX gene codes for MSAS of A. terreus.

Acyltransferases↗
PubMed1996

Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer.

In the course of our search for new antitumor agents in breast cancer, novel amino-substituted flavone derivatives were synthesized and examined for antitumor activities. Among them, 5,4'-diaminoflavone and some of its congeners showed remarkable antiproliferative activity against the estrogen receptor (ER)-positive and estrogen-responsive human breast cancer cell line MCF-7. The activity was observed irrespective of the presence or absence of estrogen. The 5-aminoflavone derivatives (5-AFs) are not classical anti-estrogens because they did not compete with [3H]estradiol to bind the estrogen receptor. Moreover, 5-AFs showed antitumor activity highly selective to the ER-positive breast cancer cell line, and they showed no effects against the ER-negative human cancer cell lines HeLa S3, WiDr, and MDA-MB-453. Although the mechanism of their selective antitumor activity to ER-positive breast cancer cells is unclear, 5-AFs are expected to be a new type of antitumor agents in breast cancer.

Antineoplastic Agents↗