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Biomedical subjects

Y Niitsu

Publications and source records attributed to Y Niitsu.

At least 163 records · Page 9Linked to original sources
PubMed1994

Serum glutathione S-transferase-pi level as a tumor marker for non-small cell lung cancer. Potential predictive value in chemotherapeutic response.

BACKGROUND: Resistance to chemotherapeutic agents is a major problem in non-small cell lung cancer (NSCLC) chemotherapy, and recent studies have indicated that glutathione S-transferase-pi (GST-pi) may play an important role in the resistance of cancer cells to alkylating agents that include platinum compound. METHODS: GST-pi in serum of 121 patients with NSCLC was measured by a sandwich enzyme-linked immunosorbent assay, and the serum concentrations of carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC) antigen, and neuron-specific enolase (NSE) were also examined. Serum levels of these tumor markers were also evaluated in relation to therapeutic response in 69 patients who received combination chemotherapy with platinum compound. RESULTS: Fifty of 121 patients with NSCLC (41.3%) showed elevated serum GST-pi levels above a cutoff value of 34.8 ng/ml (mean + two standard deviations in 30 healthy control subjects). The positive rate of GST-pi in patients with NSCLC was higher than those of CEA (37.2%), SCC (15.7%), and NSE (14.9%). The mean pretreatment GST-pi level was significantly lower in patients with a partial response to chemotherapy than in those with no response (26.9 +/- 11.3 ng/ml versus 38.8 +/- 16.7 ng/ml; P < 0.003). Among patients with elevated levels of pretreatment serum GST-pi, only 13.8% (four of 29) responded to the combination chemotherapy, whereas partial response was observed in 40.0% of patients (16 of 40) with serum GST-pi concentration below the cutoff level (P < 0.02). Neither CEA, SCC, nor NSE showed such a relationship. CONCLUSIONS: The serum GST-pi level may have limited value as a tumor marker for NSCLC: Interestingly, pretreatment serum GST-pi levels may be a useful parameter for predicting therapeutic response to combination chemotherapy regimens that include platinum compound.

Adult↗
PubMed1994

Expression and extracellular release of transferrin receptors during peripheral erythroid progenitor cell differentiation in liquid culture.

The expression and extracellular release of transferrin receptor (TR) was investigated by in vitro model system of erythroid differentiation. Human peripheral blood mononuclear cells were cultured with interleukin-3 (IL-3) for 7 days, and with erythropoietin (EPO) for an additional 8 days. After EPO stimulation, IL-3-stimulated blastic cells were serially differentiated into mature erythrocytes. [3H]-thymidine incorporation of cultured cells increased linearly from day 0 to 5, followed by a decrease. Flow cytometric analysis showed an increase of TR expression from day 0 to 5, followed by a slight decrease. By metabolic labeling with [35S]methionine and immunoprecipitation, the cell lysate exhibited a 95-kD band corresponding to the intact TR on sodium dodecyl sulfate-polyacrylamide gel electrophoresis/autoradiography at day 5, when polychromatic erythroblasts had their peak. The culture supernatant solubilized by tween-20 exhibited a 95-kD and an 85-kD band on days 5 and 8, which corresponded to the intact and the truncated forms of TR, respectively. The 95-kD band was more intense at day 5 than at day 8. The reverse transcriptase-polymerase chain reaction assay showed that the receptor-mRNA expression was parallel to receptor synthesis. Thus, the synthesis and expression of TR on erythrocytes is associated mainly with cell proliferation in the early phase, and with both cell proliferation and hemoglobin production in the middle to late phases of maturation. Concomitantly, the extracellular release of TR from erythrocytes occurs in the middle to late phases of maturation. These data suggest that polychromatic erythroblasts release soluble TR as both intact and truncated forms and may be an important source of serum TR implicated as an index for erythropoietic activity in the marrow.

Cell Differentiation↗
PubMed1994

Regulation of asialoglycoprotein receptor synthesis by inflammation-related cytokines in HepG2 cells.

The asialoglycoprotein receptor (AGPR) is responsible for the catabolism of acute phase proteins. The effects of inflammation-related cytokines on the expression of AGPR were investigated in HepG2 cells derived from a human hepatoblastoma cell line. Binding studies, using a [125I]-labeled asialo-orosomucoid ligand, revealed that AGPR numbers on cell surfaces were increased by interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). In cells treated with IL-1, IL-6, or TNF, immunohistochemical staining with an anti-AGPR monoclonal antibody demonstrated augmented expression. Pulse labeling analysis, using [35S]-labeled methionine, showed newly synthesized AGPR in both the precursor and the mature forms. When IL-1, IL-6, and TNF were added to the culture medium, total synthesis of AGPR (sum of the mature and precursor forms) was increased. In addition, the relative proportion of the synthesized precursor form of AGPR was higher in cytokine-treated than in untreated cells, suggesting that these cytokines augment the synthesis of AGPR, particularly in the stage prior to glycosylation.

Acute-Phase Proteins↗
PubMed1994

Failure of combination therapy with recombinant granulocyte colony-stimulating factor and erythropoietin in myelodysplastic syndromes.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) and erythropoietin (rhE-PO) were used to treat ten patients with myelodysplastic syndromes (MDS). None of the patients showed a favorable response in erythrocyte and platelet counts following 10 weeks' treatment, although favorable responses in neutrophil counts were observed in eight of ten patients (80.0%) and in seven of eight patients (87.5%) following 2 weeks' and 10 weeks' treatment, respectively. However, one patient with refractory anemia had a delayed favorable response in erythrocyte and neutrophil counts at week 14 in spite of the cessation of combination therapy at week 10. These results indicate that combination therapy with rhG-CSF and rhEPO is not beneficial to patients with MDS, based on the presently used protocol.

Adult↗
PubMed1994

Ethanol inhibits asialoglycoprotein receptor synthesis but augments its mRNA expression in a human hepatoma cell line.

The effect of ethanol on the expression of asialoglycoprotein receptor protein and its mRNA was studied in a human hepatoma cell line, HepG2. The number of asialoglycoprotein receptors on the cell surface was decreased to 60% of the control level, without a loss in affinity, by incubating the cells with 100 mM ethanol. The decrease in cell surface asialoglycoprotein receptors was paralleled by a decrease in total receptor numbers, including intracellular and surface receptors. The internalization of asialoglycoprotein was also diminished, to 44% of that in control cells. The decreases in cell surface receptors and total receptor numbers were partially restored by 2 mM 4-methylpyrazole, suggesting that ethanol metabolites participated in the diminution of asialoglycoprotein receptor expression. However, the steady-state expression of asialoglycoprotein receptor mRNA was increased in ethanol-treated cells and further augmented by a longer ethanol exposure. These paradoxical results, i.e., the decrease of asialoglycoprotein receptor protein and the increase of its mRNA expression, suggest that the reduction in the asialoglycoprotein receptor protein is a post-transcriptional event and that a possible feedback regulatory mechanism may control asialoglycoprotein receptor gene transcription and/or impair the degradation of its mRNA.

Alcohol Dehydrogenase↗
PubMed1994

Transforming growth factor beta 1 secreted from scirrhous gastric cancer cells is associated with excess collagen deposition in the tissue.

To explore the mechanism of increased collagen deposition in scirrhous carcinoma of the stomach, an attempt was made to define the role of transforming growth factor beta 1 (TGF-beta 1), secreted from tumour cells, as a possible humoral factor which functions in a paracrine manner to stimulate the production of collagen in regional fibroblasts. Immunohistochemical staining revealed that tumour cells in scirrhous carcinomas were generally stained more intensively than those in other types of carcinomas. On Northern blot analysis the tumour cells established from scirrhous carcinoma (KATO-III, OCUM-1 and HSC-39) exhibited relatively strong signals compared with those from non-scirrhous carcinoma (MKN-28 and MKN-45). In the culture media of scirrhous carcinoma cells, the active form of TGF-beta 1 was detected, while in those of the non-scirrhous carcinoma cells the latent form was demonstrated by both colony and radioreceptor assays. The culture medium from KATO-III showed strong stimulating activity of collagen synthesis in fibroblasts, and this activity was partially neutralised by an anti-TGF-beta 1 antibody. These results suggest that tumour cells in scirrhous carcinoma produce more active-form TGF-beta 1 than does non-scirrhous carcinoma and thus is partially responsible for the observed enhanced collagen deposition in the region.

Adenocarcinoma, Scirrhous↗
PubMed1994

Augmented systemic immunity in mice implanted with tumor necrosis factor-alpha gene-transduced Meth-A-cells.

Syngeneic BALB/c mice bearing methylcholanthrene-induced fibrosarcoma (Meth-A) cells transduced with a tumor necrosis factor (TNF) gene showed a longer life span and tumor regression as compared with mice carrying TNF-non-producing Meth-A cells. To elucidate the mechanism of the reduced tumorigenicity of TNF-producing Meth-A, we compared systemic immune responses between mice bearing high TNF producer (C5) and unmodified Meth-A cells (M0). The results indicated that the cytotoxic activity of lymphokine-activated killer cells (LAK) induced from spleen cells of mice bearing C5 was higher against both M0 and C5 than that of LAK from mice bearing M0. Also, C5 was more sensitive to LAK induced from spleen cells of C5- and M0- bearing mice than M0. We also found that cytotoxic T lymphocyte from spleen cells of mice transplanted with C5 was more cytotoxic to M0 than that from mice with M0. In addition, the population of Lyt2 (CD8)-positive T cells was higher in freshly isolated spleen cells of mice transplanted with C5 than from mice with M0. Finally, we observed a higher expression of MHC class 1 antigen on C5 than on M0. These observations suggest that the augmented host systemic immunity in mice carrying TNF gene-modified Meth-A cells is one of the mechanisms of the reduced tumorigenicity of C5 and that the increased systemic immunity can be ascribed to the increased immunogenicity of the tumor cells. Thus, the use of TNF gene-modified tumor cells as vaccines appears to be promising for therapeutic and/or prophylactic application.

Animals↗
PubMed1994

Enhancement of blood stasis and vascular permeability in Meth-A tumors by administration of hyperthermia in combination with tumor necrosis factor.

Blood stasis and vascular permeability induced by tumor necrosis factor (TNF) in Meth-A tumors transplanted in BALB/c mice were significantly enhanced by hyperthermia at 40 degrees C for 30 min immediately following TNF administration. A dose-dependent, sustained decline in the intratumoral blood flow rate occurred following the administration of TNF alone (i.v.; 5 x 10(3), 5 x 10(4), or 5 x 10(5) JRU/kg) and was enhanced by the administration of hyperthermia in combination with the TNF, even though no decline occurred with hyperthermia alone. The combination of TNF at 5 x 10(5) JRU/kg and hyperthermia resulted in a blood flow ratio (ratio of blood flow after administration to that before) of 0.47 at 1 h compared with a ratio of 0.65 at 1 h after TNF alone. The blood flow in normal skin sites did not decrease in any case. The permeability of the intratumoral vasculature similarly increased in a dose-dependent manner after the administration of TNF alone and was further increased by combination with hyperthermia, even though no increase occurred with hyperthermia alone. The mean permeability in mice receiving TNF alone at 5 x 10(5) JRU/kg was 1.35 times that in untreated mice. In mice receiving TNF at the same dose together with hyperthermia, the ratio was increased to 1.65. The results suggest that TNF selectively suppresses intratumoral blood flow, that this effect is enhanced by mild hyperthermia, and that the mechanism of the suppression by TNF with or without hyperthermia partly involves an increase in blood vessel permeability.

Animals↗
PubMed1994

Close correlation between the dephosphorylation of p53 and growth suppression by transforming growth factor-beta 1 in nasopharyngeal carcinoma cells transduced with adenovirus early region genes.

The mechanism of growth inhibition by transforming growth factor (TGF)-beta 1 was investigated. We examined the growth inhibitory effects of TGF-beta 1 on human nasopharyngeal carcinoma (KB) cells which constitutively expressed p53. TGF-beta 1 suppressed the DNA synthesis of KB cells in a dose-dependent manner. It had minimal effect on adenovirus-2-transduced KB cells expressing either adenovirus early region 1B (E1B) or 1A (E1A) product, which respectively binds to p53 or Rb product and inhibits its function, and no growth inhibition at all was observed with KB cells expressing both E1B and E1A products. Dephosphorylation of the p53 was promoted by TGF-beta 1 stimulation in KB cells, but not in E1B-producing KB cells, which sequestrate the function of p53. The growth inhibition of KB cells by TGF-beta 1 was significantly reduced by treatment with okadaic acid. These results suggest that p53 transduces the antiproliferative signal of TGF-beta 1 possibly through its dephosphorylation.

Adenovirus E1A Proteins↗
PubMed1994

Induction of synthesis of heat shock protein 72 in tumor necrosis factor gene-transduced cells.

Heat shock protein (HSP) and endogenous tumor necrosis factor (enTNF) both act as resistance factors against the cytotoxicity of various cellular stresses. To clarify the relationship between these two stress response systems, we investigated whether or not enTNF is capable of inducing HSP72. Without heating, no difference was found in HSP72 synthesis between enTNF-nonexpressing L-M cells and cells expressing L-R or L-M (pcDV-TNF). After initiation of heat treatment, however, a remarkable increase in HSP72 synthesis was noted in enTNF-expressing cells compared to enTNF-nonexpressing L-M cells. These findings indicated that enTNF augments heat-inducible HSP72 synthesis.

Animals↗
PubMed1994

Antisense oligodeoxynucleotides for IL-2, c-myc and transferrin receptor synchronize mitogen-activated lymphocytes in the G1 phase.

In order to clarify the role and interrelationship of c-myc, interleukin-2 (IL-2), and transferrin receptor (TfR) expressions on PHA-stimulated lymphocyte proliferation, we examined the effects of antisense oligodeoxynucleotides directed against c-myc, TfR, and IL-2 mRNAs on DNA synthesis and cell-cycle phase. Exposure of PHA-stimulated lymphocytes to each antisense oligomer resulted in approximately 75-80% inhibition of DNA synthesis. TfR expression was not inhibited in PHA-stimulated lymphocytes by c-myc or IL-2 antisense oligonucleotides, suggesting that the expression of c-myc, TfR, and of IL-2 is regulated by an independent mechanism. All three antisense oligonucleotides for c-myc, TfR and IL-2 synchronized mitogen-activated lymphocytes to the G1 phase as assessed by morphologic blast formation and cell-cycle phase analysis.

Base Sequence↗
PubMed1994

Specific interaction of pancreatic elastase and leucocytes to produce oxygen radicals and its implication in pancreatitis.

Many previous reports using experimental animal models of pancreatitis have suggested that oxygen free radicals play an important part in initiation and development of pancreatitis. Infiltration of inflammatory cells--that is, neutrophils, lymphocytes, and monocytes--has been seen in damaged pancreatic glands of animal models and patients with pancreatitis. As neutrophils are known to be the highest producer of oxygen free radicals among these inflammatory cells, it seems plausible that oxygen free radicals produced by neutrophils have some pathoaetiological meaning in pancreatitis. This study measured the superoxide production by neutrophils obtained from patients with acute and chronic pancreatitis and then examined the effects of pancreatic enzymes on superoxide production. Patients showed significantly higher superoxide production by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) stimulated neutrophils than healthy controls. Among the three pancreatic enzymes, amylase, trypsin, and elastase, elastase was the only one that increased the superoxide production by PMA stimulated neutrophils, by an increment of 1.5-fold. It also increased the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase prepared from PMA stimulated neutrophils by a factor of 2.1. High affinity and low affinity binding sites for elastase on neutrophils were identified. These results suggest that elastase plays a part in the development of pancreatitis by enhancing superoxide production of neutrophils.

Acute Disease↗
PubMed1994

Improved recovery of myelosuppression following chemotherapy in mice by combined administration of PSK and various cytokines.

Granulocyte-colony-stimulating factor (G-CSF), granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) were used in combination with PSK, a protein-bound polysaccharide extracted from mycelium of Coriolus versicolor (strain CM101), in myelosuppressed mice. The myelosuppression model consisted of BDF1 mice who received 150 mg/kg 5-fluorouracil (5-FU) intravenously. The peripheral blood leukocyte count during the recovery stage was significantly increased when these cytokines were administered with PSK compared to when the cytokines were used individually. In vitro colony assay revealed that the combination of PSK and any of GM-CSF, IL-3 or stem cell factor (SCF) showed a greater increase in colony numbers than when these materials were administered individually, although G-CSF did not show a synergistic effect with PSK. When bone marrow cells were obtained from mice which had been given PSK or IL-3, the colony assays were made in the presence of PSK or IL-3 in vitro. The greatest increase in the numbers was observed in colonies of the cultured group in the presence of IL-3 after the PSK priming. However, the colony formation potential of PSK was not inhibited by addition of anti-SCF antibody. The above results indicate that the combined administration of PSK with G-CSF, GM-CSF or IL-3 increased the hematological recovery of myelosuppressed mice. Moreover, the phase at which PSK has effects on hematopoietic cells seems to be at a more immature level than with IL-3. The combined administration of PSK and the above cytokines may improve myelosuppression after chemotherapy in patients with malignancy.

Animals↗
PubMed1994

Chronic idiopathic neutropenia associated with abnormal expression of granulocyte colony-stimulating factor mRNA of bone marrow stromal cells.

Chronic idiopathic neutropenia is an uncommon condition characterized by a low level of neutrophils without any causative disease. We report the details of 4 patients whose stromal cytokine mRNA expressions were examined by reverse transcription polymerase chain reaction. Three patients showed a lower expression of granulocyte colony-stimulating factor (G-CSF) mRNA both in constructive and lipopolysaccharide (LPS)-induced conditions and normal colony forming unit-granulocyte-macrophage (CFU-GM) from the bone marrow cells. One patient showed an increase of G-CSF mRNA and a decrease of CFU-GM. No abnormal expression of other cytokines including interleukin (IL)-1 beta, IL-6 and IL-8 were observed. These findings indicate that cytokine mRNA analysis of stromal cells is useful for elucidation of the etiology.

Adult↗