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Biomedical subjects

M Nishio

Publications and source records attributed to M Nishio.

At least 199 records · Page 11Linked to original sources
PubMed1994

Phase I clinical trial of irinotecan (CPT-11), 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, and cisplatin in combination with fixed dose of vindesine in advanced non-small cell lung cancer.

Irinotecan hydrochloride (CPT-11), a semisynthetic derivative of camptothecin, has been demonstrated to be active against solid tumors such as non-small cell lung cancer and colorectal cancer. Two combination phase I trials were undertaken to determine the maximum tolerated dose of CPT-11 in combination with cisplatin and vindesine in patients with advanced non-small cell lung cancer. All 46 patients (age 32-73 years) entered into these trials had a good performance status (Eastern Cooperative Oncology Group score, 0-1) and had received no prior chemotherapy or radiotherapy. In the first trial, 14 stage IV and 2 stage IIIb patients were studied; in the second trial 30 patients with stage IV disease were accrued. In the first trial, CPT-11 was given as a 90-min i.v. infusion on days 1 and 8 in combination with a fixed dose of cisplatin (100 mg/m2, i.v., on day 1) and vindesine (3 mg/m2, i.v., on days 1 and 8), every 4 weeks. The starting dose of CPT-11 was 25 mg/m2, and the dose was increased in increments of 25 mg/m2. In the second trial, the doses of either CPT-11 (days 1 and 8) or cisplatin (day 1) were escalated with a fixed dose of vindesine (same dose as the first study) given in a 4-week cycle. The starting doses of CPT-11 and cisplatin were 20 and 60 mg/m2, respectively, and the dose of either CPT-11 or cisplatin was increased in increments of 20 mg/m2. At least 3 patients were entered at each dose level in both trials. Use of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was not permitted in this trial. In the first trial, grade 4 granulocytopenia and grade > or = 3 diarrhea were dose limiting at 50 mg/m2 CPT-11, which represented the maximum tolerated dose. At the subsequent dose of CPT-11, 7 new patients were requited at the 50% reduced dose level of 37.5 mg/m2 on days 1 and 8. Nine patients were evaluated for response, and 4 of them achieved a partial response. In spite of a low dose of CPT-11 (25-37.5 mg/m2), the maximum concentration in plasma of CPT-11 (> 0.4 micrograms/ml) reached > 10-fold the in vitro concentration of CPT-11 required for 50% inhibition of growth. In the second trial, the dose-limiting toxicities were grade 4 granulocytopenia lasting for > or = 7 days and grade > or = 3 diarrhea.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Spontaneous nitric oxide release accounts for the potent pharmacological actions of FK409.

(+-)-(E)-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), which was isolated from microbial products, has been reported to show a vasorelaxant effect through a mechanism similar to that of the organic nitrates such as isosorbide dinitrate. In solution at pH 7.4, FK409 decomposed and released nitric oxide (NO) spontaneously, while isosorbide dinitrate did not. In in vitro biological tests, FK409 inhibited norepinephrine-induced contraction in rat isolated aorta more potently than did isosorbide dinitrate (ED50 = 1.0 and 310 nM, respectively) and ADP-induced human platelet aggregation (IC50 = 0.75 and > 100 microM, respectively). Nitrite/nitrate was recovered in urine accumulated for 24 h after collection from rats given FK409 or isosorbide dinitrate (10 mg/kg p.o.). FK409 (10 mg/kg p.o.) increased the plasma cyclic GMP level and at the same time decreased the mean blood pressure in conscious rats, while isosorbide dinitrate (10 mg/kg p.o.) did not change these parameters significantly. These results suggest that FK409 produces these pharmacological actions via spontaneously released NO, unlike isosorbide dinitrate, and has a possibility of becoming a unique orally active drug for cardiovascular diseases as a new NO donor.

Adenosine Diphosphate↗
PubMed1994

Molecular and biological characterization of fusion regulatory proteins (FRPs): anti-FRP mAbs induced HIV-mediated cell fusion via an integrin system.

Anti-FRP mAbs induced polykaryocyte formation of U2ME-7 cells (CD4+U937 cells transfected with the HIV gp160 gene). Anti-FRP-1 mAb immunoprecipitated gp80-85, gp120 and homodimers of these peptides, and anti-FRP-2 mAb reacted with gp135 identically to the alpha 3 subunit of integrin. Both anti-FRP-1 and anti-FRP-2 mAb-induced cell fusion was blocked by anti-beta 1 integrin antibody, fibronectin or inhibiting anti-FRP-1 antibody. Therefore, anti-FRP mAbs were thought to induce the fusion via an integrin system(s). FRP-mediated fusion was temperature, cytoskeleton, energy and Ca2+ dependent. These experiments showed a possible regulatory function of cell fusion by an integrin system(s).

Amino Acid Sequence↗
PubMed1994

Identification of mouse mammary fibroblast-derived mammary growth factor as hepatocyte growth factor.

A growth factor for normal and neoplastic mouse mammary epithelial cells in primary culture was partially purified from the conditioned medium (CM) of mouse mammary fibroblasts. The N-terminal amino acid sequence of the major 33 kD protein separated on SDS-polyacrylamide gel electrophoresis under reducing conditions suggested that the growth factor is closely related to hepatocyte growth factor (HGF). To examine whether mammary growth factor is identical to HGF we cloned mouse HGF cDNA from mammary fibroblasts using PCR with primers designed from the previously reported human and rat HGF cDNA sequences. We then expressed the cloned mouse HGF cDNA in COS-1 cells. The CM from mouse HGF cDNA-transfected COS-1 cells stimulated the growth of mammary tumor cells in a manner similar to the CM from mammary fibroblasts. From these observations it is concluded that mammary growth factor produced by mammary fibroblasts is identical to mouse HGF.

Amino Acid Sequence↗
PubMed1994

In vitro and in vivo growth of B16F10 melanoma cells transfected with interleukin-4 cDNA and gene therapy with the transfectant.

In an attempt to develop the most effective cytokine gene therapy, we transfected mouse interleukin(IL)-2, mouse IL-4, and human IL-6 cDNAs into mouse melanoma cells, B16F10. Transfection with IL-4 cDNA decreased the tumorigenicity of B16F10 most strongly. We investigated whether gene therapy with IL-4-transfected B16F10 cells was possible. Flow-cytometric analysis showed that major histocompatibility complex class I and II expression in B16F10 and IL-4-cDNA-transfected B16F10 (B16F10-IL4) cells did not differ. Doubling times of B16F10 and B16F10-IL4 were 20.1 and 21.1 h respectively. The growth of B16F10 cells was retarded if C57BL/6 mice were inoculated with B16F10-IL4 at the contralateral sides. When 5 x 10(5) B16F10 cells were transplanted subcutaneously into the flanks of C57BL/6 mice, they all developed a tumor mass, whereas no tumor masses formed in those transplanted with B16F10-IL4 cells within 60 days. No nude, severe combined immunodeficient or beige mice were able to reject parental B16F10 or B16F10-IL4 cells, although, B16F10-IL4 tumor growth in all these immunodeficient mice was slower than that of B16F10. Therefore, we concluded that T and natural killer cells are necessary for rejection of B16F10-IL4 tumor cells.

Animals↗
PubMed1994

Effect of TFC-612, a 7-thia prostaglandin E1 derivative, on intimal thickening after endothelial injury with balloon catheter in rats.

The effect of TFC-612, methyl-6-[(1R,2S,3R)-hydroxy-2-](1E,3S,5R)-3- hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl)thio] hexanoate, on intimal thickening of carotid artery 14 days after endothelium denudation with a balloon catheter was examined in rats. This compound significantly suppressed the neointimal area and the ratio of intimal and medial layer by 41.1% and 31.4%, respectively, at 3.2 micrograms/rat/h s.c. infusion. At this dose, this compound did not inhibit platelet aggregation induced by either collagen or ADP. It did not inhibit bromodeoxyuridine incorporation into medial smooth muscle cells at 3 days after injury. In in vitro experiments, TFC-612 did not inhibit the [3H]thymidine uptake into cultured smooth muscle cells, but it showed significant inhibition of smooth muscle cell migration induced by platelet-derived growth factor (PDGF) at more than 10(-9) M. This compound increased cyclic AMP levels dose dependently in cultured smooth muscle cells at more than 10(-8) M. These results suggest that TFC-612 inhibits intimal thickening by inhibition of smooth muscle cell migration from media to intima through cyclic AMP elevation.

Alprostadil↗
PubMed1994

Fusion properties of cells constitutively expressing human parainfluenza virus type 4A haemagglutinin-neuraminidase and fusion glycoproteins.

We established HeLa cell lines that constitutively expressed the fusion (F) and/or haemagglutinin-neuraminidase (HN) glycoproteins of human parainfluenza virus type 4A (PIV-4A) and used them to analyse the roles of these glycoproteins in virus-induced cell fusion. No syncytium formation occurred, even in HeLa cells expressing both the F and HN proteins (HeLa-4aF+HN cells). Also no syncytium was found in a mixed culture of cells expressing the F protein (HeLa-4aF) and the HN protein (HeLa-4aHN). Syncytia were observed in HeLa-4aF cells transfected with the HN gene, but no syncytium formation was found in HeLa-4aHN cells transfected with the F gene. Co-cultivation of HeLa-4aF+HN cells with HeLa-4aF cells generated large polykaryocytes, whereas co-cultivation with HeLa-4aHN cells induced no cell fusion. Infection of HeLa-4aF cells with PIV-4A generated large syncytia and degenerated nuclei, whereas little or no polykaryocytes were found in HeLa-4aHN cells infected with PIV-4A. From the above findings, the following conclusions were drawn: (i) the expression of both the F and HN proteins in the same cell is necessary for cell fusion; (ii) the expression of the F protein alone enhances susceptibility to cell fusion; (iii) the constitutive expression of the HN protein promotes resistance to paramyxovirus-induced cell fusion.

Cell Fusion↗
PubMed1994

HN proteins of human parainfluenza type 4A virus expressed in cell lines transfected with a cloned cDNA have an ability to induce interferon in mouse spleen cells.

Primary monkey kidney cells infected with human parainfluenza type 4A virus (HPIV-4A) were treated with various concentrations of formaldehyde. Formaldehyde (0.275%) treatment completely blocked virus production. However, when mouse spleen cells were cocultured with the fixed virus-infected cells, interferon was produced in the culture fluid. On the other hand, when mouse spleen cells were incubated with the fixed virus-infected cells in the presence of anti-HPIV-4A antiserum or a mixture of anti-HN protein monoclonal antibodies, interferon activity could scarcely be detected in the culture fluid. These findings indicated that the fixed virus-infected cells had an ability to induce interferon in mouse spleen cells and that the HN protein was related to interferon induction. Subsequently, a recombinant plasmid was constructed by inserting the cDNA of the HN gene of HPIV-4A into a pcDL-SR alpha expression vector. Mouse spleen cells produced interferon when cocultured with COS7 cells transfected with the recombinant plasmid, but did not when cocultured with COS7 cells transfected with the vector alone. Furthermore, we established HeLa cells constitutively expressing HPIV-4A HN (HeLa-4aHN cells) or F protein (HeLa-4aF cells). Type I (alpha/beta) interferon was detected in culture fluids of mouse spleen cells with HeLa-4aHN cells, but was not detected in those with HeLa-4aF cells. Therefore, it was concluded that the HN glycoproteins on the cell surface were sufficient for interferon induction to occur.

Animals↗
PubMed1994

Phase I and pharmacokinetic study of paclitaxel by 24-hour intravenous infusion.

Paclitaxel, a new antitubular agent, appears to be one of the most promising single agents for the chemotherapy of various solid tumors. The primary objectives of this phase I study of paclitaxel using 24-h continuous intravenous infusions were to determine the maximum tolerated dose of paclitaxel administered by this schedule to Japanese patients with solid tumors and to evaluate the pharmacokinetics of paclitaxel. Eighteen patients received one of five doses of paclitaxel, 49.5, 75, 105, 135 or 180 mg/m2. Premedication with diphenhydramine, dexamethasone, and ranitidine was used to prevent acute hypersensitivity reactions. Pharmacokinetic data were obtained from all 18 patients. Dose-limiting toxicities observed at 180 mg/m2 consisted of grade 4 granulocytopenia associated with grade 3 infection. No severe HSRs or cardiac toxicity were detected. Reversible toxicities observed included liver dysfunction, alopecia, peripheral neuropathy and myalgias. Pharmacokinetic studies performed using high-performance liquid chromatography demonstrated that plasma concentrations of paclitaxel increased during the 24-h infusion and declined immediately upon cessation of the infusion with a half life of 13.1-24.6 h (75-180 mg/m2). Less than 10% of paclitaxel was excreted in the urine within 72 h. The peak plasma concentrations and the areas under the concentration-versus-time curves increased linearly with the dose administered. Antitumor activity was observed in one patient with pulmonary metastasis from pharyngeal cancer. Based on these studies a phase II trial dose of 135 mg/m2 administered over 24 h was chosen.

Adolescent↗
PubMed1994

Differences in circadian photosensitivity between retinally degenerate CBA/J mice (rd/rd) and normal CBA/N mice (+/+).

Using the magnitude of phase shift of circadian locomotor rhythms induced by a single pulse of white fluorescent light, we compared the sensitivity of the circadian system to light in retinally degenerate mice and in normal mice. In the first experiment, phase response curves (PRCs) for 10-lux white light were generated in CBA/J mice with retinal degeneration (rd/rd) and CBA/N mice with normal retinas (+/+). Although large phase delays early in the subjective night and small phase advances in the late subjective night were observed in CBA/N mice, CBA/J mice showed only small phase delays early in the subjective night. In the second experiment, we found that the magnitude of phase shifts at circadian time (CT) 16 for delays and CT 24 for advances in CBA/J mice became larger with increasing light intensity, and that CBA/J mice could show the same amount of phase shift as CBA/N mice when higher intensities were used. These findings indicate that the differences in the shapes of PRCs are not due to differences in the nature of the oscillating system, but to differences in circadian photosensitivity between these strains. Because the genetic background for the rd loci was not completely identical in the CBA/N and CBA/J mice, it was possible that genes other than the rd gene might have caused different photosensitivity in these mice. Therefore, in the last experiment, we studied the circadian photosensitivity in F1 hybrids between CBA/N and CBA/J mice and in the backcross progeny with different genotypes (+/rd and rd/rd) obtained from the crossing between F1 hybrids between CBA/N and CBA/J mice and in the backcross progeny with different genotypes (+/rd and rd/rd) obtained from the crossing between F1 and CBA/J mice. In these mice with heterogeneous genetic backgrounds as well, mice with retinal degeneration were always less sensitive to light, suggesting that reduced circadian photosensitivity is caused by retinal degeneration. These results are discussed in relation to recent findings in retinally degenerate C57BL mice, which have been found to have normal circadian sensitivity to light.

Animals↗
PubMed1994

Gene therapy for Lewis lung carcinoma with tumor necrosis factor and interleukin 2 cDNAs co-transfected subline.

Gene therapy with cytokine cDNA will provide a new tool for cancer treatment. We have already reported that immunization with interleukin-2 (IL2) cDNA transfected Lewis lung carcinoma (LLC) cells induced anti-tumor immunity, which, however, was not strong enough to eradicate an established tumor. In an attempt to develop more effective gene therapy methods, we have used tumor cells co-transfected with IL-2 and tumor necrosis factor (TNF) cDNAs. These cDNAs were introduced into pBMG-Neo and pcDV-X819 vectors, respectively, and then co-transfected into LLC cells. The co-transfectants were selected by incubating them in a medium containing G418 followed by the limiting dilution method twice to obtain IL2 and TNF cDNA co-transfected LLC (LLC-TNF-IL2) cells. When 5 x 10(5)/ml LLC-TNF-IL2 cells were incubated for 48 h, they secreted 7.56 U/ml TNF and 527.0 U/ml IL2 into the culture supernatant. When C57BL/6 mice were transplanted with 1 x 10(6) LLC-TNF-IL2 cells, all the tumors were rejected. The growth of transplanted LLC, but not B16F10 melanoma cells, was retarded in mice inoculated with LLC-TNF-IL2 on their contralateral sides, which suggests specific immunity was induced. The immunization effect by the co-transfectant was superior to that of the IL2- and TNF-transfectants alone.

Animals↗
PubMed1994

[Anesthetic management of patients with dilated cardiomyopathy].

Anesthetic management of patients with dilated cardiomyopathy (DCM) was analyzed. From January 1991 to June 1993, we had 7 patients with DCM; 5 patients received general anesthesia and 2 patients received spinal anesthesia. General anesthesia was induced and maintained generally with diazepam and fentanyl. There were two patients who suffered from intraoperative arrhythmia. One patient who received spinal anesthesia suffered from ventricular fibrillation suddenly before the operation and we performed cardiopulmonary resuscitation successfully but the operation was cancelled. One patient who underwent emergency operation for gastric perforation suffered supraventricular tachycardia during the operation, and we were required to use antiarrhythmic agent that was thought to be deleterious to cardiac function. There was no patient who died perioperatively. There was one patient in the group IV of classification of Inoh which predicts the highest risk of dying from cardiac failure. In conclusion, it is important to control arrhythmia during the management of patients with DCM under anesthesia.

Adult↗
PubMed1994

[General anesthesia for patients with hypertrophic cardiomyopathy].

General anesthesia was given to six surgical patients with hypertrophic cardiomyopathy on eight occasions from 1990 to 1992. Anesthetic courses were uneventful in five patients diagnosed previously as hypertrophic cardiomyopathy. However, a patient without a diagnosis of hypertrophic cardiomyopathy had intractable cardiac arrest. A slight hypotension caused by epidural anesthesia had a devastating effect on the patient. The above experiences stress the importance of early diagnosis and careful observation in perioperative period.

Aged↗
PubMed1993

In vivo proton magnetic resonance spectroscopy study on premature aging in adult Down's syndrome.

Proton magnetic resonance spectroscopy (1H-MRS) was performed in a group of 18 adult patients with Down's syndrome (DS) aged 20-46 years, and the peak area ratios (NAA/Cr, Cho/Cr, NAA/Cho) of N-acetylaspartate (NAA), total creatine (Cr), and choline-containing compounds (Cho) calculated separately in the patients in their 20's, 30's, and 40's. In age-matched healthy control groups, there were no significant age-related changes in any of the peak area ratios. In contrast, in the DS group, although the relative amount of NAA (NAA/Cr) showed no significant change with increasing age, the relative amount of Cho (Cho/Cr and NAA/Cho) was significantly increased in the 40's group. At least as judged by MRI, few age-related general morphological changes such as brain atrophy were apparent in the third, fourth, and fifth decade groups. However, the MRI findings considered together with the age-related changes in the peak area ratios suggest that in DS patients in the fifth decade metabolic abnormalities such as degradation and/or rapid synthesis of brain cell membrane may occur prior to neuronal loss and degeneration.

Adult↗
PubMed1993

Antigenic and molecular properties of Murayama virus isolated from cynomolgus monkeys: the virus is closely related to avian paramyxovirus type 2.

A new virus that belonged to a member of paramyxovirus was isolated from cynomolgus monkeys showing respiratory disorders about 20 years ago and was named Murayama virus (MrV). Interestingly, it showed no serological relationship with the mammalian paramyxoviruses tested. On the other hand, it was related to Yucaipa (YuV) and Bangor virus (BaV) belonging to avian paramyxovirus type 2 (PMV2). In analysis using anti-MrV monoclonal antibodies, MrV showed the closest relationship with YuV, and furthermore some conserved epitopes were found among avian paramyxovirus, MrV, YuV, BaV, and Newcastle disease virus (NDV). Subsequently, the nucleotide sequences of the F and HN genes of MrV were determined. In comparison with the deduced amino acid sequence of MrV and other paramyxoviruses, MrV showed the highest homology with NDV and higher similarity to HPIV2 group rather than to HPIV1 group. The present study clearly indicates that MrV belongs to PMV2 adapting to monkeys.

Amino Acid Sequence↗