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Biomedical subjects

S Sugawara

Publications and source records attributed to S Sugawara.

At least 19 recordsLinked to original sources
PubMed1992

The preclinical safety evaluation of human monoclonal antibody against cytomegalovirus.

The human monoclonal antibody against cytomegalovirus (Mab C23) was examined pharmacokinetically and toxicologically as part of the preclinical studies prior to approval for human use. Rats given repeated intravenous administrations of Mab C23 produced no antibodies against Mab C23 and maintained a blood Mab C23 level in a dose-dependent manner. However, pregnant rabbits produced antibodies against Mab C23. The half-life of Mab C23 in plasma was 15.9 days in rats, which was similar to that of normal human serum gamma-globulin (NHSG). Neither behavioral effects nor circulatory disturbance was found in mice, rats, and dogs even after a single intravenous injection of 100 or 200 mg/kg, which corresponds to 50 or 100 times the intended clinical dosage. The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasions with 1- or 2-week intervals elicited a transient decrease in leukocyte counts in rats given 10 or 20 mg/kg, but no adverse effects in cynomolgus monkeys. Mab C23 did not cause any reproductive or developmental toxicity when administered to rats and rabbits at dose levels of 20 mg/kg or less. However, pregnant animals showed lower plasma levels of Mab C23 than non-pregnant animals. The chromosomal aberration test disclosed no clastogenicity in human lymphocytes. An immunostaining for Mab C23 revealed no localizations in several tissues of cynomolgus monkeys given intravenous doses of Mab C23.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Changes in serum erythropoietin levels during chemotherapy for lung cancer.

Serial serum erythropoietin (EPO) levels were measured in 12 adult lung cancer patients during cancer chemotherapy. In major cases, EPO levels increased significantly after chemotherapy while the hemoglobin (Hb) remained at initial levels. EPO fell gradually or rapidly to initial levels after a peak, although the patients were anemic. The increase of EPO levels was linearly related to the decrease in Hb (y = 17.48x + 1.003). The mechanism of the rapid increase of EPO is not simply explained by anemia, but might be related to new synthesis, corresponding to depressed bone marrow.

Adult↗
PubMed1992

Protein kinase C activity in human leukemia cell lines with reference to sensitivity to antineoplastic agents.

Protein kinase C (PKC) regulates many cellular processes. In view of its possible relevance to the drug resistance, the levels of PKC activity were assessed in human leukemia cell lines with reference to the sensitivity to antineoplastic agents. K562/ADM exhibited approximately 2-fold higher levels of PKC activity as compared with the parental K562. After a 1-hr preincubation with Adriamycin (ADM) (0.5, 1, 10 microM), PKC activity in K562 tended to increase dose-dependently, while no substantial alteration was found in K562/ADM. Cisplatin (CDDP) or etoposide was of no effect. The activity in THP-1/E was slightly lower than THP-1, and the basal level stayed unchanged with any one of the above drugs. These results suggest that in K562 increase in PKC activity with ADM may play a role in the process of acquisition of resistance.

Antineoplastic Agents↗
PubMed1992

Chemotherapy in small cell lung cancer--from view point of dose intensity.

Results of chemotherapy trials for small cell lung cancer carried out for the past 5 years were analyzed from view point of dose intensity. Early study of CDDP+EP+ADM (1985 to 1987) showed moderate response rate (RR) of 72% with MST of 369 days. Succeeding alternative protocol of CDDP+EP+VCR/CPM+ADM+MTX (1989-1990) showed improved RR of 88% and MST of 13 months. Actual dose and interval for the alternating regimen was superior to the single arm regimen. Projected relative dose intensity against MAOP protocol including 6 drugs common to our regimen was 0.86 and delivered RDI was 0.61 with comparable RR and MST. The results may indicate that change of dose intensity within the conventional range does not result in major advantage or disadvantage for substantial prolongation of the survival in SCLC patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Differences in development of bovine oocytes recovered by aspiration or by mincing.

This experiment was performed to clarify relationships between conditions of bovine ovaries and developmental capacity of the follicular oocytes recovered from them and to compare two methods of oocyte collection, aspiration and mincing. Follicular oocytes with surrounding intact, unexpanded cumulus recovered by follicular aspiration or by mincing of tissue from 24 pairs of ovaries were matured and fertilized in vitro. The number of follicular oocytes recovered from pairs of ovaries averaged 32.1 +/- 3.2, but the number recovered varied greatly among the 24 pairs of ovaries (range, 7 to 71). The overall rate of development to the blastocyst stage was 18% (137/771), and the average number of blastocysts produced from a pair of ovaries was 5.7 +/- 1.1 (range, 0 to 17). No relationships were found between the presence of corpora lutea or large follicles and the proportion of oocytes capable of reaching the blastocyst stage in vitro. However, a positive correlation was observed between the number of oocytes obtained from each pair of ovaries and subsequent in vitro development; the correlation was especially high for oocytes obtained by aspiration. These data suggest that the developmental capacity of bovine follicular oocytes after in vitro maturation and fertilization is correlated to the number of antral follicles aspirated from the pair of ovaries.

Animals↗
PubMed1992

[Clinical significance of respiratory infections associated with lung cancer patients].

An attempt was made to interpret the clinical significance of secondary infections associated with lung cancer. The incidence of secondary infections was 51.4% in 214 in-patients with lung cancer in our institution in 1988 and 1989, and almost all of them had respiratory infections caused by commonly encountered bacteria. The incidence of infection was high in lung cancer of cell types other than adenocarcinoma, and in those with hypoalbuminemia, impaired cellular immunity and obstruction of the airway. The prognosis in patients with infection was much poorer than that in patients without infection. Major pathogens responsible for infection were Staphylococcus aureus including methicillin-resistant S. aureus (MRSA), Haemophilus influenzae, Klebsiella spp. and Pseudomonas aeruginosa. These pathogens, except for H. influenzae, were isolated in the terminal stage in cases with airway obstruction and post cancer chemotherapy. The efficacy rate of 194 therapeutic regimens against infection was 57.7%. It was thus found that the efficacy rate in 1988 and 1989 exceeded that in the 1970s. The effectiveness was very poor for infections caused by S. aureus and P. aeruginosa, and for cases with airway obstruction and marked impairment of pulmonary blood flow. The efficacy rate of single-drug regimens was 57.1% (80/140) and that of combined regimens was 59.3% (32/54). The above results indicate that a new combined therapy which includes a beta-lactam antibiotic as well as measures to improve the general health of compromised hosts are required in the treatment of secondary infections in these patients.

Adult↗
PubMed1991

Nicotinamide and 3-aminobenzamide interfere with receptor-mediated transmembrane signaling in murine cytotoxic T cells: independence of Golgi reorientation from calcium mobilization and inositol phosphate generation.

The two competitive inhibitors of ADP-ribosylation, nicotinamide and 3-aminobenzamide, have been reported to interfere with TNF-induced cell apoptosis, and there is evidence that they inhibit killer-induced target cell lysis as well. There are very few drugs known to specifically interfere with target apoptosis induced by killer cells. We therefore sought to explore the effects these inhibitors have on CTL-mediated cell lysis. Here we show that TcR-mediated transmembrane signaling in CTL, measured by Ca2+ mobilization and generation of inositol phosphates, is inhibited by nicotinamide. The possibility that all cell functions are suppressed by the drug is excluded by the finding that constitutive secretion of BLT serine esterase is not inhibited, whereas stimulated secretion of this enzyme is suppressed. We also show that nicotinamide does not interfere with CTL target cell binding or reorientation of the Golgi apparatus toward the target binding site. It is concluded that nicotinamide inhibits transmembrane signaling in CTL and thereby interferes with delivery of the lethal hit to targets.

Animals↗
PubMed1990

Effects of stress on lysability of tumor targets by cytotoxic T cells and tumor necrosis factor.

The effects of stress on four tumor cell lines are analyzed in view of the possibility that stress protects tumor cells against immune attack. We show that stress causes resistance to CTL and TNF in two cell lines. Induction of resistance is time dependent and reversible and not due to failure of killer cells to interact with stressed targets. It is shown that stress induces stress proteins concomitant with induction of resistance to killer cells and TNF. Moreover experiments are presented suggesting that resistance to either immune effector is due to independent mechanisms. The conclusion that stress can induce mechanisms in targets that interfere with the action of TNF as well as with target lysis following a lethal hit by CTL is discussed.

Animals↗
PubMed1990

[A case of double primary malignancy of intracranial germinoma and thymoma controlled by radiotherapy].

We report a case of double primary malignancy, in which intracranial germinoma and thymoma occurred successively and independently. As curative therapies, the former lesion was treated by definitive irradiation and the latter by postoperative irradiation. Excellent local control has been maintained for 79 and 49 months, respectively, since the beginning of the radiotherapy. The accumulated dose to the thoracic spinal cord was 63.5 Gy. No symptoms suggesting the onset of radiation myelopathy, the most critical late radiation injury, have been observed up to now. We also investigated radiobiological effect to the spinal cord assessed by the formulae of CRE and TDF.

Adult↗
PubMed1990

Evidence for differentiation of NK1+ cells into cytotoxic T cells during acute rejection of allogeneic bone marrow grafts.

The ability of lethally irradiated C57BL/6 mice to acutely reject H-2d bone marrow is due to a lymphocyte population that is NK1+, ASGM1+, CD4-, CD8-, CD3+. Transfer of spleen cells from C57BL/6 mice expressing these antigens into nonresponder 129 mice adoptively transfers the ability to reject H-2d marrow grafts. The specificity of this rejection maps to the H-2D major histocompatibility complex (MHC) region. Transplantation of high doses of H-2d marrow into C57BL/6 overrides the acute rejection mechanism leading to graft survival. During growth of the graft, a cytolytic activity develops that is due to ASGM1+, CD8+ cytolytic T lymphocytes (CTLs) with H-2Ld specificity. The possibility that the ASGM1+, CD8+ CTLs are descendents of the CD3+, NK1+, ASGM1+, CD8- cells responsible for acute rejection is investigated by adoptive cell transfer experiments. We show that beige mice that lack NK1+ cells as well as the ability to acutely reject H-2d marrow fail to generate specific CTLs after transplantation with a high dose of H-2d marrow. Transfer of highly purified NK1+ cells from B6.PL-Ly-2a/Ly-3a (Lyt-2.1) into beige mice together with H-2d marrow leads to generation of Lyt-2.1 CTLs from donor NK1+ cells. These results show that specific CTLs are generated from NK1+ cells during acute marrow graft rejection.

Animals↗
PubMed1990

Differential effects of protein synthesis inhibition on CTL and targets in cell-mediated cytotoxicity.

The reactions that lead to target cell lysis by cytotoxic T cells (CTL) are despite intensive investigations poorly understood. To examine the relative roles effectors and targets play in the lytic reaction, protein synthesis in either CTL or targets was inhibited before assay of lysis. We show, in agreement with previous results, that de novo protein synthesis is not necessary in either effectors or targets during the cytolytic reaction. However, activation of CTL requires protein synthesis. Activated CTL respond to protein synthesis inhibitors with a cycling of activity, a result that is interpreted to be consistent with a stimulus secretion mechanism. Treatment of targets with protein synthesis inhibitors prior to incubation with CTL leads to a very rapid and irreversible loss of lytic susceptibility. It is shown that the decrease in lysability is not due to lack of proper CTL target interaction: MHC class I antigens are expressed on drug-treated targets and these cells serve as cold targets in competitive inhibition experiments. Moreover, drug-treated targets trigger transient Ca2+ mobilization and generation of inositol phosphates in CTL. It is therefore concluded that drug-treated targets are able to trigger CTL function but lack a component that is required for their successful lysis.

Animals↗
PubMed1990

Induction of human TCR gamma delta + and TCR gamma delta-CD2+CD3- double negative lymphocytes by bacterial stimulation.

When human blood mononuclear cells (MNC) were incubated with heat-killed bacteria, proliferation of MNC was observed 5 days after stimulation, showing a peak on day 7. Interestingly, the bioassay of the culture supernatant and Northern blot analysis of mRNA demonstrated that no IL-2 production was associated with these proliferative responses. The induced lymphoblasts consisted predominantly of TCR gamma delta + (22.4 +/- 9.3%) and TCR gamma delta-CD2+CD3-(33.2 +/- 11.8%) double negative lymphocytes (n = 10), which were initially minor populations (less than 10%) in freshly isolated MNC. The prominent induction of TCR gamma delta + cells was confirmed by Northern blot analysis. TCR gamma delta + cells induced by bacterial stimulation seemed to generate from lymphocytes lacking the apparent expression of gamma delta TCR. The inducing capability for double negative cells is present in a large number of species of bacteria, especially Gram-positive bacteria. Gel filtration analysis of ultrasonicated filtrates of Staphylococcus aureus and Streptococcus pyogenes revealed that a substance with an Mr of 25-26 kd could be substituted for whole bacterial particles in the cell proliferative responses. In contrast to the purified protein derivative (PPD)-induced response, the response described here was inducible in the cord blood of neonates who had not yet been exposed to the corresponding bacterial infection. The physicochemical properties of the sonicated filtrates were different from those of PPD. These results suggested that the present phenomenon may be nonspecific, polyclonal (or oligoclonal) activation of TCR gamma delta + and TCR gamma delta -CD2+CD3- cells by bacterial stimulation.

Adult↗
PubMed1990

[The Sistrunk median cervical cyst operation using a cecal foramen pointer].

The cecal foramen pointer was invented for a Sistrunk median cervical cyst operation. The instrument consists of three elements, namely: The cecal foramen holder, the giraffe shaped connector and the pointer needle. First of all, the cecal foramen is held by the holder which is reconstructed from hemostatic forceps. The one end of the connector is joined to the holder's handle. Then the other end of the connector comes along the patient's chin, in front of the neck. The cyst and mid-portion of the hyoid bone are dissected, followed by coring out of the thyroglossal duct toward the cecal foramen. In the coring out process, the pointer needle is pierced through the tunnel of the connector's opposite end, so that the needle top reaches to the bottom of operative wound. Then the needle shows exactly the direction to the cecal foramen and the distance from the bottom of the wound to the cecal foramen. By using this instrument the operation was successfully performed for a case of a recurrent median cervical cyst with a complete fistula to the cecal foramen.

Humans↗
PubMed1989

Analysis of mechanisms by which NK cells acquire increased cytotoxicity against class I MHC-eliminated targets.

Acid treatment, where cells are exposed to 0.2 M citric acid buffer at pH 3 for 2 min, was described in a previous paper to be a method which specifically eliminates class I MHC antigens from the membrane of viable cells. We applied this method to characterize functional roles of class I MHC antigens on the target cells in NK cell cytotoxicity. When NK target cells, U937, Molt-4, and Raji, were subjected to acid treatment, the treated cells lost their surface class I MHC antigens and became more sensitive to NK cell killing. On the other hand, the susceptibility of K562 cells which initially lacked class I MHC antigens did not significantly change after such treatment. We then examined the mechanism which enables NK cells to become more cytotoxic against class I MHC antigen-eliminated target cells. Single cell binding assay and cold target inhibition assay demonstrated that class I MHC antigen-eliminated target cells did not acquire high binding affinity to NK cells. However, the interaction between NK cells and class I MHC antigen-eliminated targets resulted in a greater increase in production of NKCF-like factor than did the interaction between NK cells and untreated targets. Class I MHC antigen-eliminated targets did not acquire high killer susceptibility to NKCF-like factor. The present study utilizing the acid treatment method confirmed that surface class I MHC antigens on the targets are important immunoregulatory molecules not only for cytotoxic T lymphocytes but also for NK cells and elucidated some of the underlying mechanisms.

Acids↗
PubMed1989

Establishment of an etoposide (VP-16)-resistant subline of THP-1 human monocytic leukemia cell line.

A VP-16-resistant subline was established from THP-1 human monocytic leukemia cells by subculturing in stepwise increasing concentrations of the drug. The resistant cells (THP-1/E) were capable of sustaining continuous growth in 1.0 microgram/ml VP-16. The 50% inhibition dose (IC50) was 1.4 micrograms/ml or a 35-fold of the parent cells. A more than 18-fold IC50 was also obtained with teniposide (VM-26). However, no substantial cross-resistance was observed with 5 other antineoplastic drugs, IC50 values being limited below several times of THP-1.

Cell Division↗
PubMed1989

Epidermodysplasia verruciformis accompanied by large granular lymphocytosis. Report of a case and immunological studies.

A 34-year-old man with epidermodysplasia verruciformis showed increased natural killer (NK) cell activity in his peripheral blood cells, which was found to be due to abnormal expansion of large granular lymphocytes (LGL). Surface marker analysis of LGL in a two-color immunofluorescence test demonstrated that all LGL subsets, Leu-7+11-, Leu-7+11+, and Leu-7-11+, were increased. In contrast, his peripheral blood mononuclear cells showed a remarkable decrease in response to T cell mitogens, which could not be restored by depletion of the LGL subpopulation from the mononuclear cells. Immunohistologic studies for dermal distribution of LGL showed numerous Leu-7+ cells but no Leu-11+ cells at the sites of delayed hypersensitivity reaction or interferon beta- or interferon gamma-injected sites. These findings suggest that the elevated NK cell activity in this patient with epidermodysplasia verruciformis was caused by overall expansion of normal LGL subpopulations, but that the decreased T-cell mitogenic response represented a primary T-cell defect rather than a direct suppression by increased NK cells. It is noteworthy that despite this extraordinary increase of all LGL subpopulations in the blood, Leu-11+ NK cells never appeared in the skin.

Adult↗