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Biomedical subjects

Y Niitsu

Publications and source records attributed to Y Niitsu.

At least 235 records · Page 13Linked to original sources
PubMed1991

[Intraperitoneal administration of cis-platin with arterial infusion chemotherapy of advanced and recurrent gastric cancer].

Arterial infusion therapy was used for 97 patients with AMF therapy. Forty were unresectable, 30 non-curatively resected and 22 recurrent gastric cancers. 5-fluorouracil (5-FU) was administered by arterial continuous infusion, adriamycin (ADM) and mitomycin C (MMC) by bolus infusion in the hospital, and continuous arterial 5-FU infusion and ADM low dose intermittent bolus infusion chemotherapy (AF therapy) was used for outpatients. The clinical effectiveness was evaluated. One year cumulative survival rate of primary case by Kaplan Meier method was 21.6%, and that of recurrent gastric cancer was 4.5%. The median survival periods were 7 months in primary cases and 4 months in recurrent cases. In primary cases, the arterial infusion therapy was more effective in non-curatively resected cases than in unresectable ones. Intraperitoneal administration of cisplatin with AF intraarterial infusion therapy (AF-CDDP therapy) was applied in 11 cases with 9 primary and 2 recurrent cases. The clinical effectiveness of each was evaluated. One-year cumulative survival rate of primary case by Kaplan-Meier method was 28.6% and the median survival periods were 10 months. AF-CDDP therapy was considered more effective for unresectable gastric cancer with carcinomatous peritonitis. In conclusion, our method is considered to be advantageous in the treatment of carcinomatous peritonitis of gastric cancer patients.

Adult↗
PubMed1991

[A remarkable effect of K-18 (IgG-melphalan complex) in a case of RAEB with hypoplastic marrow].

A 63-year-old male with refractory anemia with excess of blasts (RAEB) and hypoplastic marrow was treated with K-18 (240 mg/day P.O.). On admission, peripheral blood revealed pancytopenia. Bone marrow specimen revealed severe hypocellularity with 18.9% of the blast cells. Ten months later, the blast cells in the bone marrow decreased to 3.8%, and complete remission (CR) was obtained. CR was eight weeks. Duration of response (CR + PR) continued for about eight months. K-18 is an antitumor agent with minimal side effects, and seems to be effective for RAEB with hypoplastic marrow.

Anemia, Refractory, with Excess of Blasts↗
PubMed1990

Suppressive effects of intracellular glutathione on hydroxyl radical production induced by tumor necrosis factor.

Protective effects of intracellular glutathione (GSH) against the cytotoxicity of human recombinant tumor necrosis factor (TNF) were investigated. Three tumor cell lines (L-M, B-16, HeLa) were used as target cells. Exposure of these cells to buthionine sulfoximine (BSO) or diethyl maleate (DEM) resulted in the depletion of intracellular GSH content to 5.2-43.0% of control values and enhancement of their susceptibility to TNF cytotoxicity. The hydroxyl radical production in L-M cells stimulated by TNF was increased by treatment with BSO or DEM. These results are consistent with the suggestion that intracellular GSH exerts its protective function against the cytocidal effect of TNF by inhibiting the hydroxyl radical production stimulated by TNF.

Animals↗
PubMed1990

Inhibition of neutrophil migration by tumor necrosis factor. Ex vivo and in vivo studies in comparison with in vitro effect.

Coincubation of neutrophils with TNF inhibited the chemoattractant-directed migration of neutrophils under agarose and enhanced their migration in the multiwell chemotaxis chamber. To assess the physiological significance of these differing in vitro TNF effects, ex vivo and in vivo investigations were performed using animal models. Neutrophils from the peripheral blood of rabbits preadministered systemic TNF showed impaired ability to migrate toward chemoattractants in vitro. In addition, systemic TNF administration suppressed zymosan-activated plasma-induced local accumulation of leukocytes in mouse skin. The results indicate that circulating TNF may act as a suppressor for local inflammatory reaction.

Animals↗
PubMed1990

Expression of endogenous tumor necrosis factor as a protective protein against the cytotoxicity of exogenous tumor necrosis factor.

Based on the finding that expression of endogenous tumor necrosis factor (TNF) which is not detected in TNF-susceptible cells was observed in TNF-resistant cells, the assumption was made that endogenous TNF may be a protective protein against the cytotoxic activity of TNF. In order to confirm this possibility, we investigated the relationship between expression of endogenous TNF and TNF susceptibility by using the gene transfection method. When L-M, TNF-highly sensitive murine fibrosarcoma cells were transfected with a human TNF gene, the stable transfectants expressed endogenous TNF and acquired resistance to TNF. Conversely, when endogenous TNF synthesis was inhibited by introducing an antisense TNF gene into HeLa, TNF-less sensitive human cervical cancer cells, the sensitivity was enhanced. These findings indicate that endogenous TNF is one of the protective factors against the cytotoxic activity of TNF.

Animals↗
PubMed1990

The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis.

Acute myelofibrosis is often associated with acute megakaryoblastic leukemia (AMKBL). Although the exact mechanism for the progression of myelofibrosis in AMKBL is unclear, certain humoral factors from megakaryoblastic cells, the precursors of platelets, may be involved in the enhancement of collagen synthesis by bone marrow fibroblasts. The present study, therefore, is an investigation of the possible pathogenic role of transforming growth factor-beta (TGF-beta), known to be a very potent collagen-stimulating factor found in platelets in the myelofibrosis of AMKBL. The results obtained were as follows: (1) Conditioned media from peripheral megakaryoblasts taken from an AMKBL patient and from established megakaryoblast cell lines (MEG-01) had much greater stimulatory effects on collagen synthesis in bone marrow fibroblasts than conditioned media from other leukemic cell types. (2) Based on an assessment of soft agar colony formation, there was greater TGF-beta activity in media that had been conditioned from megakaryoblasts than in media from other leukemic cell types. (3) When compared with other leukemic-cell types, megakaryoblasts showed substantially greater expression of TGF-beta mRNA that was hybridized at 2.5 kb with a TGF-beta cDNA probe, and TGF-beta polypeptides were detected at 13 Kd with anti-TGF-beta antibodies. (4) The addition of the anti-TGF-beta antibody inhibited the stimulatory effects of the megakaryoblast conditioned medium on collagen synthesis in bone marrow fibroblasts. These results clearly suggest that megakaryoblasts produce and secrete an active form of TGF-beta and stimulate collagen synthesis in bone marrow fibroblasts in a paracrine manner.

Animals↗
PubMed1990

Effect of tumour necrosis factor in the mouse-tail model of psoriasis.

The effects of local and systemic administration of tumour necrosis factor (TNF) on the mouse-tail model of psoriasis were examined histologically at 4 days after administration. Subcutaneous injection of TNF at 1 x 10(1) to 1 x 10(4) units/mouse resulted in dose-dependent formation of a granular layer in the tail scales, which was quantified as the percentage of tail scales having granular layer formations extending over half or more of their surface and was larger than that occurring in untreated mice and in mice receiving injections of vehicle solution alone. Daily intraperitoneal injection of TNF at 1 x 10(3) or 1 x 10(4) units/mouse for 28 days resulted in similar granular layer formation and in a significantly reduced mitotic index of the tail keratinocytes, indicating an antiproliferative effect of TNF. The lowered mitotic index and the induction of granular layers, apparently attributable to a modulation of keratinocyte proliferation and differentiation by TNF, suggest that TNF may be effective as a drug for treatment of psoriasis.

Animals↗
PubMed1990

Determination of antigenic epitopes recognized by four monoclonal antibodies to glutathione S-transferase pi (GST-pi).

Four independent antibodies (6A, 5F, 2H and 2F) to Glutathione S-transferase pi (GST-pi) were selected to characterize their epitopes. Amino acid analysis of 5.6 K and 7.4 K tryptic peptides appeared to suggest that the epitope recognized by antibodies 2H and 2F is located in the N-terminal 44 peptides of GST-pi, and that of 6A and 5F is located in the C-terminal 69 peptides. Reactivities of antibodies 6A and 5F with two synthetic peptides indicated that 6A recognized an epitope in the C-terminal hydrophilic fragment 176Leu-209Gln, and could be distinguished from 5F which recognized an epitope in the 141Thr-176Leu hydrophobic fragment. The differential immuno-reactivity of antibodies 6A and 5F with GST-pi itself, was characterized by the particularly high reactivity of 6A and almost no reactivity of 5F with the natural conformation of GST-pi in solution. This may be explained by differences in the hydropathic natures of their epitopes. The 6A antibody was useful for immunodetection of GST-pi in circulation, while 5F was found to be most suitable for histochemical staining of tumor tissue.

Amino Acid Sequence↗
PubMed1990

[Receptor-mediated cancer therapy--tumoricidal cytokines, adoptive therapy of LAK, TIL].

Three modes of receptor-mediated cancer therapy were reviewed presenting our own data. Employment of tumoricidal cytokines (IFN, TNF, LT) to this type of therapy has been expected to be the most promising approach. However, preclinical and clinical results so far obtained, revealed that they were useful only for the very limited diseases including renal cancer or some hematological malignancies. Second approach is to utilize growth factors conjugated with toxin or carzinostatin which are readily internalized into tumor cells. In this context, transferrin-neocarzinostatin was examined in our laboratory both in vitro and in vivo for its anticancer activity and was found to suppress tumor growth more significantly than neocarzinostatin alone on the basis of molar ratio. Thus this approach may be worthy to be clinically investigated. Adoptive therapy of lymphokine activated killer (LAK) or tumor infiltrating lymphocyte (TIL) may also be categorized into receptor mediated cancer treatment since both are activated by signals through IL-2 receptor. Although clinical evaluation is still on going, the therapy appears to be effective only when effector cells are administered locally to tumors.

Humans↗
PubMed1990

[Tumoricidal biological response modifiers (BRM)].

TNF, IFN, LT and IL-1 are well-known biological response modifiers (BRM) with cytocidal activity. Whereas carcinostatic agents generally derive their cytocidal action from their direct mutual reaction with target molecules (e.g., DNA, RNA), the cytocidal action of BRM resides in the enzyme response which ensures upon their binding to receptors. Accordingly, concomitant use of these drug of differing mechanism of action has a rationale. Considering that a certain kind of counteracting protein is present in cancer cells which are refractory or resistant to such cytokines, combination therapy with carcinostatic agents with inhibitive activity against such protein is also justified. In the same context the effects of TIL and LAK activated by IL-2 could be enhanced if the immune system should be modulated by combined use of BRM and carcinostatic agents such as CY. This paper discusses the results obtained with BRM and carcinostatic agents in combination in animal models and clinical cases.

Antineoplastic Agents↗
PubMed1990

[IBL like T cell lymphoma associated with hemolytic anemia and polyploidy chromosomal abnormality--a case report].

A 56-year-old man was admitted to Sapporo Kitano Hospital on May 30, 1987 because of fever, retention of ascites and pleural effusion, generalized lymphnode swelling and hepatosplenomegaly. Laboratory findings showed Coombs' positive hemolytic anemia, leukocytosis and polyclonal hypergammaglobulinemia. Serological test included positive RA factor, anti-DNA 16 U/ml, thyroglobulin Ab 1600 x and microsome Ab 3200 x. A cervical lymphnode specimen exhibited typical histologic picture of IBL like T cell lymphoma. The surface markers of lymphoma cells were CD2(+), CD8(+) and CD4(-). Chromosomal analysis of these cells revealed polyploidy abnormality for all chromosomes except for No. 14's which are disomy. All lymphoma cells have XXY sex chromosome and mar1, mar2, mar3. Gene rearrangement for beta-chain of T cell receptor was proved in these lymphoma cells. He was treated with prednisolone, vincristine, cyclophosphamide, adriamycin etc, but died of respiratory failure 171 days after admission. We reported a rare case of IBL like T cell lymphoma with polyploidy chromosomal abnormality accompanied with hemolytic anemia.

Anemia, Hemolytic↗
PubMed1990

[Acute megakaryoblastic leukemia with complex chromosomal aberrations].

A case of acute megakaryoblastic leukemia with complex chromosomal aberrations is reported. A 63-year-old man was admitted to our hospital because of pancytopenia. Bone marrow aspiration resulted in a dry tap and biopsy showed hypoplastic marrow with fibrosis. Blast cells in the peripheral blood were identified as megakaryoblasts because they were positive for electron microscopic platelet peroxidase (PPO). In addition, monoclonal antibody, TP80, to platelet glycoprotein II b-III a reacted with in about 26% of the blast cells. Chromosomal analysis of the peripheral blood revealed a mosaic pattern of a normal karyotype and abnormal ones, including 44, XY, -5, -7, -18, 10q-, +marker.

Chromosome Aberrations↗
PubMed1989

Intracellular hydroxyl radical production induced by recombinant human tumor necrosis factor and its implication in the killing of tumor cells in vitro.

This study investigated the effect of recombinant human tumor necrosis factor (rhTNF) on hydroxyl radical production by established cell lines in vitro, and its implication in the killing of tumor cells by rhTNF. During incubation of TNF sensitive mouse tumorigenic fibroblast L-M cells (2 X 10(7) cells) in the presence of rhTNF (100 U), hydroxyl radical production as detected by the evolution of methane gas from dimethyl sulfoxide increased gradually, at 18 h reaching 1.8 times that in the absence of rhTNF. This increase was dependent on the concentration of rhTNF and was effectively prevented by the simultaneous addition of anti-rhTNF monoclonal antibody III 2F3, which inhibited both the binding of rhTNF to its receptor and the cytotoxic activity of rhTNF. The addition of iron chelator 2,2'-bipyridine, which inhibits iron-catalized Fenton reaction and so inhibits hydroxyl radical generation, suppressed both the increase of hydroxyl radical production and the cytotoxicity induced by rhTNF. A similar increase in hydroxyl radical production in the presence of rhTNF was also detected with TNF-sensitive human myosarcoma-derived KYM cells, but no such increase was detected with TNF insensitive human embryonic lung fibroblast HEL cells. The results show that rhTNF induces increased hydroxyl radical production in TNF-sensitive cells, and suggest that this plays an important role in the mechanism of tumor cell killing by rhTNF.

2,2'-Dipyridyl↗
PubMed1989

Serum glutathione-S-transferase-pi as a tumor marker for gastrointestinal malignancies.

A glutathione-S-transferase-pi (GST-pi) immunoradiometric assay was devised as a potential marker for serodiagnosis of malignant disease. Elevated serum GST-pi levels were observed in patients with various gastrointestinal malignancies including gastric, esophageal, colonic, pancreatic, hepatocellular, and biliary tract cancers. Patients with benign gastrointestinal diseases had normal GST-pi, but some patients with chronic hepatitis and cirrhosis had slightly elevated levels. Over 80% of patients with Stage III or IV gastric cancer and even about 50% of those with Stage I and II had elevated serum GST-pi. After surgery serum GST-pi levels returned to normal. Resected stomach cancers were immunohistochemically positive for GST-pi. During chemotherapy of colonic, gastric, and hepatocellular cancers with a series of different drugs, GST-pi changed in a biphasic manner; increases during initial phases of therapy may reflect acquisition of drug resistance by the tumor. In general, serum GST-pi assays provide a sensitive and reliable marker for gastrointestinal malignancies.

Biomarkers, Tumor↗
PubMed1989

Signalling pathway of tumor necrosis factor in normal and tumor cells.

Several aspects of the activity and effects of tumor necrosis factor (TNF) were investigated to gain further insight into its cytotoxic mechanism. The relation between number of TNF receptors and TNF susceptibility of both tumor cells and normal cells was studied, utilizing a specific binding assay. Among the tumor cells, a fairly close correlation (r = 0.855) was observed between receptor number and sensitivity to TNF. No cytotoxic effect by TNF was observed on any of the normal cells tested, even though TNF receptors were shown to be present, and cell proliferation was apparently stimulated by TNF in some cases. TNF internalization and intracellular distribution were studied by pulse-labelling and Percoll density gradient centrifugation. In L-M (murine tumorigenic fibroblasts, highly sensitive to TNF cytotoxicity) cells and HEL (human embryonic lung cells, non-sensitive to TNF cytotoxicity) cells, receptor-bound 125I-labelled recombinant human TNF was rapidly internalized and delivered to lysosomes within 15-30 min, and this was followed by degradation and release into the culture medium. The presence of either a cytoskeletal disrupting agent or a lysosomotropic agent was observed to inhibit the cytotoxic effect of TNF, thus also indicating that TNF internalization, followed by delivery to lysosomes, is essential in the cytolytic mechanism of TNF. As observed by [3H]uridine incorporation, TNF did not affect RNA synthesis in L-R cells (TNF-resistant cell lines derived from L-M cells) and HEL cells, but markedly stimulated (by 3.5 times) RNA synthesis in L-M cells.

Animals↗