Biomedical subjects

T Mayumi

Publications and source records attributed to T Mayumi.

At least 73 records · Page 4Linked to original sources

PubMed1999

Specific binding of TES-23 antibody to tumour vascular endothelium in mice, rats and human cancer tissue: a novel drug carrier for cancer targeting therapy.

The tissue distribution of anti-tumour vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles from isolated rat tumour-derived endothelial cells (TECs) was assessed in various tumour-bearing animals. Radiolabelled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, the source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumour tissue in nude mice, radioactivities of 125I-labelled TES-23 were also up to 50 times higher than those of control antibody with little distribution to normal tissues. The selective recognition of TES-23 to TECs was competitively blocked by preadministration of unlabelled TES-23 in vivo. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in oesophagus cancers. These results indicate that tumour vascular endothelial cells express common antigen in different tumour types of various animal species. In order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its anti-tumour effect in rats bearing KMT-17 fibrosarcomas. The immunoconjugate (TES-23-NCS) caused marked regression of the tumour, accompanied by haemorrhagic necrosis. Thus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumour vascular endothelium and its application to many types of cancer.

Adenocarcinoma↗

PubMed1999

Low-dose intramuscular polymyxin B improves survival of septic rats.

UNLABELLED: Polymyxin B (PLB) is a cationic antibiotic that also stoichiometrically neutralizes the lipid A moiety of endotoxin. We examined effects of a small dose of PLB on the mortality of rats with cecal ligation and puncture, on LPS-stimulated nitric oxide (NO) production, and on tumor necrosis factor alpha (TNF alpha) production by isolated rat Kupffer cells. MATERIALS AND METHODS: In vivo studies: Cecal ligation and puncture (CLP) was performed under anesthesia in 28 rats. One hour after CLP, either 600 U/kg of PLB or saline was administered intramuscularly every 6 h (PLB group: n = 12; control group: n = 16). Plasma endotoxin was measured at 3 and 24 h after the CLP by the Endospecy test. This was compared with survival. IN VITRO STUDIES: Kupffer cells were isolated from the normal rat liver. The cells were incubated with LPS or LPS + PLB. After 24 h, NO and TNF alpha content were measured using the Griess and ELISA methods, respectively. RESULTS: Low dose PLB significantly decreased the endotoxin levels at both 3 and 24 h (5.5 +/- 2.1 pg/mL vs. 32.8 +/- 3.6 at 3 h; 26.1 +/- 6.1 vs. 49.1 +/- 5.6 at 24 h (p < .05) after CLP. PLB significantly improved survival of CLP rats (68.8% in the control group vs. 100% in the PLB treated group on 3 days after CLP, p < .001). PLB also attenuated NO and TNF alpha production from the Kupffer cells. CONCLUSION: Intramuscular PLB administered in low doses may improve the mortality of sepsis.

Animals↗

PubMed1999

Bleeding induced interleukin-6 decreases blood loss via activation of coagulation.

Hemorrhage is known to induce the production of inflammatory cytokines such as interleukin-6 (IL-6). IL-6 plays an intermediate role as a factor in the activation of coagulation cascade and exerts a lethal effect in sepsis. To examine the effect of endogenous IL-6 on blood loss, we performed four experiments in female ddY mice. Enzyme immunoassay using an uncontrolled hemorrhage model, i.e., 75% tail resection, revealed the production of serum IL-6 (Experiment 1). We also measured cumulative blood loss and survival rate (Experiment 2); measured blood pressure and performed thrombelastogram (TEG) (Experiment 3); and measured plasma thrombin-antithrombin III (TAT) complex levels in two groups, one pretreated with 1 mg of anti-IL-6 monoclonal antibody (mAb), and one with normal rat globulin (NRG) using the same model (Experiment 4). The mAb group showed a significantly higher blood loss than the NRG group. All mice survived for 5 days in both groups. Blood pressure did not differ between either group. The TEG results suggest that administration of anti-IL-6 mAb caused mild suppression of coagulation activation, but did not affect fibrinolysis or platelets. In the mAb group, plasma TAT complex concentrations showed a significant decrease compared with the NRG group. In conclusion, hemorrhage-induced IL-6 may contribute to hemostasis through activation of coagulation, thus reducing blood loss.

Animals↗

PubMed1999

Prolongation of the effective duration of cytomedical therapy by re-injecting SK2 hybridoma cells microencapsulated within alginate-poly(L)lysine-alginate membranes into human interleukin-6 transgenic mice.

We previously reported that SK2 hybridoma cells that secreted anti-human interleukin-6 (hIL-6) monoclonal antibodies (SK2 mAb) were microencapsulated within alginate-poly(L)lysine-alginate (APA) membranes (APA-SK2 cells) for immunoisolation, and a single intraperitoneal injection of these APA-SK2 cells remarkably improved IgG1 plasmacytosis in hIL-6 transgenic mice (hIL-6 Tgm). However, the duration of the effectiveness of APA-SK2 cells as a cytomedicine was unfortunately limited. In this study, we attempted to re-inject APA-SK2 cells into hIL-6 Tgm for the purpose of prolonging the cytomedical therapy. In hIL-6 Tgm re-injected with APA-SK2 cells, the plasma IgG1 level did not show any increase in 37 week old mice, and their survival time was at least three times longer than those of untreated hIL-6 Tgm. These results suggest that re-injected APA-SK2 cells survived and secreted SK2 mAb in the allogeneic mice. Thus, the limited duration of the cytomedical effects of APA-SK2 cells was probably caused by the disappearance of the inner space of microcapsules for cell proliferation, not by the rejection of the host's immune system. Therefore, if we can regulate the proliferation of the cells microencapsulated within a semipermeable membrane, we may be able to develop a cytomedicine which will continue its function longer after a single injection.

Alginates↗

PubMed1999

Regioselective conjugation of chitosan with a laminin-related peptide, Tyr-Ile-Gly-Ser-Arg, and evaluation of its inhibitory effect on experimental cancer metastasis.

A conjugate from the YIGSR peptide and chitosan has been prepared on the basis of a regioselective modification strategy of chitosan, and its antimetastatic activity has been assayed. Chitosan was converted to its organosoluble derivative, 6-O-trityl-chitosan, in 3 steps, and then coupled with the peptide portion containing a spacer amino acid, Ac-Tyr-Ile-Gly-Ser-Arg-beta Ala-OH [beta Ala; beta-alanine]. The product was treated with CHCl2CO2H to afford the desired conjugate, Ac-Tyr-Ile-Gly-Ser-Arg-beta Ala-chitosan, which proved to inhibit the experimental lung metastasis of B16BL6 melanoma cells in mice at lower doses than the parent peptide.

Animals↗

PubMed1999

[A patient operated for occlusion of the superior mesenteric artery].

A 40-year-old woman presented with fever, dysarthria, and left hemiparesis. Diagnostic imaging detected an infarction in the right cerebrum; lupus anticoagulant was positive. A T4N3M0 adenocarcinoma coexisted in the left lung, which was irradiated once. Two days later, the superior mesenteric artery was occluded. The bowel was widely resected but she died of hepatic infarction. The lung cancer may have triggered catastrophic antiphospholipid syndrome.

Adenocarcinoma↗

PubMed1999

[Pulmonary tumor mass aberration into the bronchus of the intact right lung during total left lung resection].

A 77-year-old male with lung cancer underwent a total left lung resection. During surgery, there was no ventilatory trouble such as hypoventilation or hypoxia. However, a mass was found in the right main bronchus by endobronchial fiberscopy before extubation. Because the mass could not be aspirated through the endobronchial fiberscope, we extracted it using basket-foreceps. We speculated that surgical procedures may have caused the tumor mass to move to the bronchus of the contralateral intact lung. Accordingly, fiberscopic examination of the airway before extubation should be mandatory, even if there is no ventilatory trouble during lung resection.

Aged↗

PubMed1999

Enhanced antitumor potency of polyethylene glycolylated tumor necrosis factor-alpha: a novel polymer-conjugation technique with a reversible amino-protective reagent.

We attempted to develop a novel method for the chemical modification of cytokines with synthetic polymers to increase in vivo therapeutic efficacy. A pH-reversible amino-protective reagent, dimethylmaleic anhydride (DMMAn), was used for polymer conjugation of tumor necrosis factor-alpha (TNF-alpha) with polyethylene glycol (PEG). The novel PEGylated TNF-alpha, PEG-TNF-alpha(+), which was pretreated with DMMAn before PEGylation, had 20% to 40% higher specific activity than PEG-TNF-alpha(-) (not treated with DMMAn) in vitro. Moreover, PEG-TNF-alpha(+) more potently caused tumor necrosis in Meth-A solid tumors in mice than did PEG-TNF-alpha(-). The middle fraction (M) of PEG-TNF-alpha(+), which was of the optimal degree of modification among PEG-TNF-alpha(+)s with different molecular weights, caused the highest degree of tumor hemorrhagic necrosis: 30-fold higher than native TNF-alpha and 2-fold higher than the most potent MPEG-TNF-alpha(-) that also had nearly the same molecular weight. Significantly, improvements in antitumor activity in vivo were more marked than were changes in specific activity. Furthermore, native TNF-alpha caused a dose-dependent body weight loss in mice, whereas no obvious side effects were observed in any PEG-TNF-alpha-treated mice. These results suggest that PEGylation using DMMAn is a useful for clinical cytokine delivery.

Animals↗

PubMed1999

[Critical appraisal of treatments in emergency settings].

A critical appraisal was carried out of treatment with high-dose epinephrine (HDE) in cardiopulmonary resuscitation (CPR), active compression and decompression CPR (ACD-CPR), military antishock trousers (MAST), and Continuous renal replacement therapy (CRRT) in the emergency setting, based on evidence-based medicine. Although the pathophysiological rationale encourage the clinical application of these treatments to improve the long-term outcome (mortality), no clinical trial could confirm their benefit. Additionally, Japanese investigators have reported no clinical epidemiological study related to this issue. Thus a clinicoepidemiological study associated with treatments in critical settings is required in this country.

Emergencies↗

PubMed1998

Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes into the artery that leads to tumors.

We report that tumor necrosis factor (TNF) alpha induced a strong antitumor immune reaction when it was produced in arteries leading to tumors by gene transfer in vivo. We used a mouse model carrying a sarcoma-180 tumor in the right footpad and injected the fusogenic liposomes encapsulating the human TNF-alpha gene into the right femoral artery. Under this condition, human TNF-alpha was detected only in the artery leading to the tumor and in the tumor. There was a significant regression in tumor growth when the TNF-alpha gene was delivered into the right femoral artery, with 4 of 11 mice completely cured. No regression was observed when the TNF-alpha gene was delivered into the left femoral artery or into the tumor or when the luciferase gene was administered. Tumor regression was inhibited by the injection of anti-TNF-alpha, anti-CD4, or anti-CD8 monoclonal antibody, and CD8+ T cells accumulated in the tumors of TNF-alpha-treated mice. These results suggest that TNF-alpha expressed locally in the arteries leading to tumors efficiently suppresses tumor growth through reinforcement of an antitumor immune reaction. The significance of this phenomenon for cancer gene therapy was discussed.

Animals↗

PubMed1998

Identification of tumor vascular antigens by monoclonal antibodies prepared from rat-tumor-derived endothelial cells.

We have reported the isolation and specific in vitro properties of tumor-derived endothelial cells (TEC) from rat KMT-17 fibrosarcomas transplanted into rats. To develop antibody-based tumor vascular targeting therapy for solid tumors, we have generated monoclonal antibodies (MAbs) using passive immunization of outside-out membrane vesicles of rat epididymal-fat-pad-derived capillary endothelial cells (FCEC) followed by active immunization of those of rat TEC. The MAbs produced were screened against TEC and FCEC. Of all cultured hybridomas, 75 (3.3%) of the secreted MAbs preferentially recognized TEC. We selected a total of 7 MAbs which detected antigens highly abundant in TEC, although 5 of the 7 MAbs were weakly positive for FCEC in cell-ELISA and FACS analyses. The antigens recognized by these MAbs, with the exception of MAb TES-7, were present on endothelial cells of tumor blood vessels in KMT-17 fibrosarcoma tissues, as shown by immunohistochemical analysis. Antigens of 40- and 80-kDa were recognized by MAbs TES-1, 7, 17, 21 and 26 and by MAbs TES-23 and 27 respectively. Although the function of these antigens, which are preferentially expressed on rat tumor-derived endothelial cells, is still unknown, we believe that future studies of such antigens will help elucidate the role of endothelial cells in tumor vasculature. Our results indicate that MAbs may provide a novel tool for the development of antibody-based therapy targeting tumor vasculature.

Animals↗

PubMed1998

Tryprostatin A, a specific and novel inhibitor of microtubule assembly.

We have investigated the cell cycle inhibition mechanism and primary target of tryprostatin A (TPS-A) purified from Aspergillus fumigatus. TPS-A inhibited cell cycle progression of asynchronously cultured 3Y1 cells in the M phase in a dose- and time-dependent manner. In contrast, TPS-B (the demethoxy analogue of TPS-A) showed cell-cycle non-specific inhibition on cell growth even though it inhibited cell growth at lower concentrations than TPS-A. TPS-A treatment induced the reversible disruption of the cytoplasmic microtubules of 3Y1 cells as observed by indirect immunofluorescence microscopy in the range of concentrations that specifically inhibited M-phase progression. TPS-A inhibited the assembly in vitro of microtubules purified from bovine brains (40% inhibition at 250 microM); however, there was little or no effect on the self-assembly of purified tubulin when polymerization was induced by glutamate even at 250 microM TPS-A. TPS-A did not inhibit assembly promoted by taxol or by digestion of the C-terminal domain of tubulin. However, TPS-A blocked the tubulin assembly induced by inducers interacting with the C-terminal domain, microtubule-associated protein 2 (MAP2), tau and poly-(l-lysine). These results indicate that TPS-A is a novel inhibitor of MAP-dependent microtubule assembly and, through the disruption of the microtubule spindle, specifically inhibits cell cycle progression at the M phase.

Animals↗

PubMed1998

Amino acids and peptides. XXXIII. A bifunctional poly(ethylene glycol) hybrid of laminin-related peptides.

A novel amino acid type poly(ethylene glycol) (aaPEG) was prepared and its application as a drug-carrier was examined. The peptides, Pro-Asp-Ser-Gly-Arg (PDSGR) and Tyr-Ile-Gly-Ser-Arg (YIGSR) which are active fragments of Laminin (a cell adhesion protein), were previously reported to be inhibitors of experimental metastasis. Both peptides were conjugated with aaPEG (average molecular weight, 3,000) to prepare a bifunctional peptide-PEG hybrid. The hybrid, PDSGR-aaPEG-YIGSR, was manually prepared by the solid-phase fluorenylmethyloxycarbonyl (Fmoc) strategy. The antimetastatic activity of the peptides in mice was not lost when conjugated to form a larger aaPEG molecule. YIGSR(375 nmol) and PDSGR (375 nmol and 750 nmol) did not demonstrate antimetastatic activity, but a mixture of PDSGR (187 nnmol) and YIGSR (187 nmol) exhibited an inhibitory effect. The inhibitory effect of the hybrid (187 nmol) was more potent than that of the mixture (PDSGR and YIGSR), indicating that the inhibitory effect of the peptides was potentiated by hybrid formation with aaPEG.

Animals↗

PubMed1998

Cell cycle arrest and antitumor activity of pironetin and its derivatives.

The biological effects of pironetin and its derivatives on cell cycle progression and antitumor activity were studied. At 10-20 ng/ml, both pironetin and its demethyl derivative, NK10958P completely inhibited the cell proliferation of 3Y1 cells, however, epoxypironetin showed only a weak inhibitory activity. The cell cycle analysis revealed that these compounds arrested the cell cycle progression at the M-phase in a dose-dependent manner. These antiproliferative effects of pironetin were also observed in the range 5-25 ng/ml with several tumor cell lines. In CDF1-SLC mice bearing P388 leukemia cells, the intraperitoneal administration of 6.3 mg/kg pironetin over a 5-day period showed a moderate antitumor effect (T/C, 128%). As the chemical structure of pironetin is different from other M-phase inhibitors such as colchicine or vinblastine, pironetin will be the lead compound for a potential new antitumor drug.

Animals↗

PubMed1998

Antitumor activity of tumor necrosis factor alpha conjugated with divinyl ether and maleic anhydride copolymer on solid tumors in mice.

The purpose of this study is to further explore the usefulness of conjugation with functional polymeric modifiers for clinical application of bioactive proteins and to increase the therapeutic efficacy of tumor necrosis factor alpha (TNF-alpha) by conjugation in vivo. We synthesized TNF-alpha conjugated with the copolymer of divinyl ether and maleic anhydride (DIVEMA), which has intrinsic antitumor activity as a synthetic biological response modifier. The synthesis of DIVEMA-TNF-alpha could be controlled by the addition of 2,3-dimethylmaleic anhydride (DMMAn), which binds to or separates from amino groups when the pH is changed. The specific activity of DIVEMA-TNF-alpha (+) synthesized with DMMAn was hardly decreased in vitro. However, DIVEMA-TNF-alpha (-), which is conjugated without blocking by DMMAn, had a markedly diminished specific activity. DIVEMA-TNF-alpha (+) caused a dramatic hemorrhagic necrotic effect on the tumor when compared to native TNF-alpha 24 h after i.v. injection into mice bearing Sarcoma-180 solid tumors. In addition, DIVEMA-TNF-alpha (+) at a dose of only 100 Japan reference units per mouse revealed a dramatic antitumor effect that is approximately 100 times greater than native TNF-alpha and that could induce complete regression in all five mice bearing Meth-A solid tumors without any apparent side effects. Because neither DIVEMA alone nor a mixture of TNF-alpha and DIVEMA caused antitumor activity with i.v. administration, the increase in antitumor potency of TNF-alpha may be caused by the covalent conjugation with DIVEMA. DIVEMA-TNF-alpha at low dose revealed dramatic antitumor potency. Because TNF-alpha injected in vivo is extremely low-dose, concentration of intrinsic TNF-alpha in vivo is not influenced. Therefore, the cytokine network in vivo is not destroyed. These results suggest that DIVEMA is a useful polymeric modifier for conjugation of TNF-alpha to increase its antitumor activity.

Animals↗

PubMed1998

Gene transfer vectors based on Sendai virus.

A gene delivery system is a fundamental technology used in human gene therapy. In order to treat patients suffering from incurable metabolic diseases, we must be able to deliver genes efficiently in situ and induce stable gene expression in non-dividing tissue cells. However, none of the current gene transfer systems (both viral and non-viral) satisfies this goal. In order to develop a novel gene delivery system that is free from the defects of existing gene transfer vectors, we analyzed natural biological phenomena that involve gene transfer and expression, and made artificial components that mimic the functioning of these systems. Our recent results shed light on three major aspects of gene transfer and expression: (1) the direct delivery of DNA into cytoplasm using fusogenic liposomes, (2) the transfer of DNA from cytoplasm to nucleus with a nuclear localization signal, and (3) the stabilization of DNA in the nucleus as an independent replicon. The possible development of a hybrid vector by combining these components is discussed.

Cell Nucleus↗

PubMed1998

Involvement of CD4+ T cells in the development of dextran sulfate sodium-induced experimental colitis and suppressive effect of IgG on their action.

1. To clarify the role of T cells in the development of dextran sulfate sodium (DSS)-induced colitis, T cells from colitis mice were primed with DSS-pulsed macrophages in vitro and then transferred into normal mice. In addition, to determine whether the target cell of immunoglobulin G (IgG) is the T cell, the extent of T cell proliferation induced by pulsed macrophages was examined after preincubation with IgG. 2. When mice receiving the primed T cells were treated with oral DSS, colitis symptoms were more severe than in animals treated with oral DSS only. This activity of primed T cells was reduced by depletion from the cells of CD4+ but not CD8+ cells. 3. The proliferation of T cells from colitis mice induced by pulsed macrophages was inhibited by T cell preincubation with homologous IgG. 4. The results suggest that CD4+ T cells play an important role in the development of DSS-induced experimental colitis and that IgG may modulate the development of colitis through interaction with pathogenic T cells.

Adoptive Transfer↗

PubMed1998

Effect of ultrafiltration during cardiopulmonary bypass for pediatric cardiac surgery.

The effect of ultrafiltration during cardiopulmonary bypass (CPB) was evaluated for correcting ventricular septal defects with associated pulmonary hypertension in patients less than 18 months old. Interleukin (IL)-6 and IL-8 concentrations in the blood, ultrafiltrate, and urine were measured. The blood IL-6 concentration increased to 128.4+/-20.2 pg/ml by the end of surgery, which is lower than the concentration seen in adult patients (273.1+/-48.2 pg/ml, p < 0.02). The blood IL-8 concentration was not significantly different than that of adults. The total amounts of excreted IL-6 in the ultrafiltrate and urine during CPB were 11.5+/-0.32 pg/kg and 0.32+/-0.07 pg/kg, respectively (p < 0.05). The total amounts of excreted IL-8 in the ultrafiltrate and urine were 4.64+/-0.69 pg/kg and 1.92+/-0.56 pg/kg, respectively (p < 0.05). No differences were seen in these values for excretion between children and adults. We conclude that ultrafiltration during CPB in pediatric patients is more effective in removing proinflammatory cytokines than in adults and more effective than renal filtration alone.

Cardiopulmonary Bypass↗