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Biomedical subjects

K Nakagawa

Publications and source records attributed to K Nakagawa.

At least 19 recordsLinked to original sources
PubMed1992

Substrate specificity and distribution of UDP-GalNAc:sialylparagloboside N-acetylgalactosaminyltransferase in the human stomach.

The detailed substrate specificity of the UDP-GalNAc:sialylparagloboside N-acetylgalactosaminyltransferase to form the Sd(a+) blood group active carbohydrate determinant GalNAc beta 1-4(NeuAc alpha 2-3)Gal was studied using a membrane fraction prepared from human gastric fundic mucosa. Various sialosylated oligosaccharides and gangliosides were examined as acceptor substrates. Oligosaccharide substrates were fluorescence-labelled with 2-aminopyridine, and the transferase activity was quantified by h.p.l.c. using a reversed-phase column. The structures of the products were determined by glycosidase degradation and proton n.m.r. 3'-Sialyl-lactose (II3NeuAcLac), 3'-sialyl-lactotetraose (IV3NeuAcLc4), and 3'-sialyl-lactoneotetraose (IV3NeuAcnLc4) were good substrates for the beta 1-4GalNAc transferase in gastric fundic mucosa, but 6'-sialyl-lactoneotetraose (IV6NeuAcnLc4) or 6'-sialyl-lactose (II6NeuAcLac) were not. Gangliosides with a terminal NeuAc alpha 2-3Gal residue such as GM3, sialylparagloboside, GM1b and GD1a were also studied. The activity of beta 1-4GalNAc transfer to sialylparagloboside was much higher than that to GM2, GM1b or GD1a in spite of them having the same terminal residue. Measurement of the activity of the beta 1-4GalNAc transferase in biopsy specimens demonstrated that the activity was localized in gastric fundic mucosa and was absent in pyloric mucosa, intestinal metaplasia and gastric cancer tissue. Thus the beta 1-4GalNAc transferase present specifically in fundic mucosa required a NeuAc alpha 2-3Gal residue connected to either type-1-chain or type-2-chain oligosaccharides. In glycolipids, the acceptor specificity was restricted to NeuAc alpha 2-3Gal beta 1-4GlcNAc because the NeuAc alpha 2-3Gal beta 1-3GalNAc structure in ganglio-series glycolipids was not a good acceptor substrate.

Aminopyridines↗
PubMed1992

Proto-oncogene c-jun and c-fos messenger RNAs increase in the liver of carnitine-deficient juvenile visceral steatosis (jvs) mice.

We determined the mRNA levels of c-jun and c-fos in the liver of C3H-H-2 degrees jvs mice. Both were higher in jvs mice than in normal mice. The level of c-jun mRNA increased gradually after birth, but in the control mice there was almost no change. In addition, alpha-fetoprotein and aldolase A mRNA levels were also higher than in normal littermates. These results suggest that the pattern of the gene expression in jvs mice partly resembles the one that occurs in undifferentiated hepatocytes and/or hepatocellular carcinoma.

Aging↗
PubMed1992

Allelotype of non-small cell lung carcinoma--comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma.

We examined loss of heterozygosity (LOH) on all autosomal chromosomes in 53 non-small cell lung carcinomas. Frequent LOH was observed on the long arms of chromosomes 1 (37%), 2 (31%), 5 (30%), 8 (31%), and 13 (32%), and the short arms of chromosomes 3 (54%) and 17 (62%). LOH on chromosomes 3p and 17p was observed in all informative cases of squamous cell carcinoma, but was significantly less frequent in adenocarcinomas (P = 0.003 and 0.001, respectively). Similarly, LOH on chromosome 13q was observed frequently in squamous cell carcinomas (5 of 9 informative cases, or 56%), but in only 5 of 26, or 19%, of adenocarcinomas. In contrast, LOH on chromosome 2q was observed only in adenocarcinomas. In addition, this chromosomal arm was lost more frequently in poorly differentiated, compared to well differentiated adenocarcinomas. Furthermore, a correlation between fractional allelic loss and pathohistological grade was identified. These results implicate the presence of several tumor suppressor genes associated with development and/or progression of non-small cell lung carcinomas.

Adenocarcinoma↗
PubMed1992

Mechanism of cross-resistance to a camptothecin analogue (CPT-11) in a human ovarian cancer cell line selected by cisplatin.

We established a cisplatin-resistant human ovarian cancer cell line (HAC2/0.1) from the parent cell line (HAC2/P) by continuous exposure of HAC2/P to 0.1 microgram of cisplatin/ml. Drug sensitivity determined by colony assay revealed that HAC2/0.1 was 2.4 times as resistant to cisplatin as the parental cell line. HAC2/0.1 was 12.1 and 2.0 times as resistant to (4s)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)-carbony loxy]dione hydrochloride trithydrate (CPT-11) and 7-ethyl-10-hydroxy-CPT (SN-38; an active metabolite of CPT-11), respectively, than HAC2/P. We studied the mechanism of cross-resistance to CPT-11 in HAC2/0.1. The glutathione (GSH) content was higher in HAC2/0.1 than in HAC2/P. The activity of DNA topoisomerase I and the accumulation of CPT-11 and SN-38 were also the same. On the other hand, the conversion of CPT-11 to SN-38 in HAC2/0.1 was about 3-fold less than in HAC2/P. Treatment of the parent and resistant cell lines with buthionine sulfoxamine (BSO) decreased the GSH content of both cell lines and decreased the 50% inhibitory concentrations of all the tested drugs for HAC2/0.1. The accumulation of CPT-11 in HAC2/0.1 but not in HAC2/P was increased by BSO treatment. On the other hand, in HAC2/P the 50% inhibitory concentrations of SN-38 and CPT-11 were not influenced by BSO treatment. The 50% inhibitory concentration of CPT-11 for HAC2/0.1 was not reduced by BSO treatment to the level for HAC2/P, even though the GSH content had been reduced more than in HAC2/P. These results show that there is no clear relationship between GSH and resistance to CPT-11. The decreased conversion of CPT-11 to SN-38 is considered to be the main cause of resistance to CPT-11 in this cell line.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Participation of poly(ADP-ribose) polymerase in the drug sensitivity in human lung cancer cell lines.

Poly(ADP-ribose) polymerase has been generally assumed to be involved in DNA repair. The level of the enzyme in various lung cancer cell lines was examined to determine if it is involved in drug resistance. Among nine cell lines of lung cancer tested, small-cell lung cancer lines, which showed higher sensitivity to cisplatin and etoposide, were unexpectedly found to contain significantly higher poly(ADP-ribose) polymerase activity than five non-small-cell lung cancer cell lines. This activity inversely correlated with IC50 values of lung cancer cell lines to etoposide, an inhibitor of topoisomerase II. The polymerase activity was also examined in several cisplatin-resistant variants of the cell lines. However, no difference was observed between parental and cisplatin-resistant cells. There was no significant relation between poly(ADP-ribose) polymerase activity and IC50 values for cisplatin and carboplatin. Although this enzyme was considered to play some role in the resistance to specific drugs, it might not be a critical factor in cisplatin-induced cytotoxicity.

Antineoplastic Agents↗
PubMed1992

Modification by phenobarbital of decreased glutathione content and glutathione S-transferase activity in livers of lead-treated mice.

Lead acetate (100 mg/kg) administered i.p. to male mice decreased hepatic glutathione (GSH) content and also glutathione S-transferase (GST) activity. However, the liver GSH content of mice treated with both lead and phenobarbital (80 mg/kg, i.p.) remained unchanged, whereas their GST activities were higher than the controls. Phenobarbital antagonized the Pb-induced decrease in liver adenosine triphosphate content. Additionally, phenobarbital shortened the half-life of hepatic GSH determined using buthionine sulfoximine, an inhibitor of GSH synthesis. Acceleration of hepatic GSH turnover by phenobarbital possibly diminishes the Pb-induced impairment of GSH-conjugation of xenobiotics.

Adenosine Triphosphate↗
PubMed1992

Direct observation of laser generated free radicals from a myocardium target site.

The first direct observation of unstable free radicals generated by laser irradiation of myocardium samples has been performed by EPR at 100 K. Characteristic iron signals are measured for pulsed laser ablation of the sample. The EPR results are discussed in relation to the relative efficiency of the various types of lasers to produce free radicals. A comparison is made of the types of free radicals produced by the action of pulsed vs continuous wave (cw) laser energy.

Electron Spin Resonance Spectroscopy↗
PubMed1992

Effects of granulocyte colony-stimulating factor, interleukin-1 alpha, and interleukin-6 on prolonged myelosuppression induced by nimustine hydrochloride in rats.

The myelorestorative effects of granulocyte colony-stimulating factor (G-CSF), interleukin-1 alpha (IL-1 alpha) and interleukin-6 (IL-6) were studied in F-344 rats which had been treated with cyclophosphamide (CY), carboplatin (CBDCA), or nimustine hydrochloride (ACNU). In CY- or CBDCA-pretreated rats, significantly higher peripheral white blood cell (WBC) count was observed in animals treated with G-CSF and IL-1 alpha, while the platelet (PLT) count was elevated by IL-6 treatment. All of the cytokines had little effect on the hemoglobin (HB) value. Animals treated with ACNU had prolonged myelosuppression. Treatment of these animals with G-CSF and IL-1 alpha significantly enhanced the recovery of HB value as well as WBC count. Higher PLT counts were observed in treated groups, but a statistical difference was not evident. Combination therapy with G-CSF and IL-1 alpha, G-CSF and IL-6, or IL-1 alpha and IL-6 did not have any significant beneficial effects on the peripheral blood cell count in ACNU-pretreated rats over single agent therapy. Conversely, the combination of IL-6 and G-CSF had an unfavorable effect on HB and PLT levels. In rats which received multiple doses of ACNU, G-CSF treatment exhibited a beneficial effect on WBC, HB, and PLT levels, the most prominent on the HB value. These findings suggest that treatment with hematopoietic cytokines may be most beneficial when combined with anticancer drugs which are known to cause prolonged myelosuppression.

Animals↗
PubMed1992

Secondary T-cell lymphoma presenting as a giant ulcer.

Secondary cutaneous T-cell lymphoma may present with various types of skin lesions, but rarely produces ulceration in contrast to primary cutaneous T-cell lymphoma. We report a case of malignant lymphoma of the tonsil that recurred as a giant cutaneous ulcer on the back of a 45-year-old man. Biopsy of the ulcer revealed a malignant lymphoma of diffuse, mixed-cell type. Surface marker analysis of the tumour cells showed suppressor/cytotoxic T-cell characteristics. The skin lesions were treated by electron beam therapy.

Humans↗
PubMed1992

Adsorption of nafamostat mesilate by hemodialysis membranes.

The adsorption of the anticoagulant nafamostat mesilate (FUT-175) by five different hemodialysis membranes was studied in vivo and in vitro. In vivo, FUT-175 was adsorbed strongly by a polyacrylonitrile (AN69) membrane and slightly by another polyacrylonitrile (J-PAN) membrane but not by Cuprophan (CU), hemophan (HE), or polymethylmethacrylate (PMMA) membranes during hemodialysis performed in 4 patients in whom FUT-175 was used as an anticoagulant. Only during hemodialysis using the AN69 membrane did FUT-175 not induce a significant prolongation of celite-activated coagulation time. In vitro studies showed that FUT-175 was adsorbed by the AN69, J-PAN, and PMMA membranes but not by the CU and HE membranes. Methylene blue, a dye that possesses a cationic portion in its chemical structure, stained AN69, J-PAN, and PMMA membranes. Since FUT-175 also possesses a cationic portion, we conclude that FUT-175 is adsorbed by negatively charged membranes via an ionic bond and is unsuited for use as an anticoagulant in hemodialysis using an AN69 membrane because of that membrane's marked capacity to adsorb FUT-175.

Adsorption↗
PubMed1992

CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer.

PURPOSE: The purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed. RESULTS: Significant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major toxic effects were leukopenia and diarrhea. There were 14 partial responses (54%) among the 26 patients. CONCLUSIONS: A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities. The recommended dose for phase II studies is 60 mg/m2 of CPT-11 on days 1, 8, and 15, and 80 mg/m2 of cisplatin on day 1 every 4 weeks.

Adult↗
PubMed1992

CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer.

PURPOSE: To evaluate the activity of CPT-11, which is a new derivative of camptothecin, against refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Sixteen patients with refractory or relapsed SCLC were entered onto a prospective, non-randomized, single-institution phase II trial. All 16 patients had been pretreated heavily with some form of cisplatin-based combination chemotherapy. Five patients had received previous chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide (CODE) as an induction therapy. Six patients had been treated with concurrent cisplatin and etoposide plus chest x-ray. The median time off chemotherapy was 7.3 months (range, 1.9 to 15.1 months). Patients were treated with a CPT-11 starting dose of 100 mg/m2 body surface given as a 90-minute intravenous (IV) infusion every week with subsequent doses based on toxicity. Fifteen patients were assessable for toxicity, response, and survival. RESULTS: Seven patients (47%; 95% confidence limits for an overall response rate, 21.4% to 71.9%) responded to CPT-11 with a median duration of response of 58 days. The major toxicities were myelosuppression (predominantly leukopenia), diarrhea, and pulmonary toxicity. CONCLUSION: CPT-11 is an active agent against refractory or relapsed SCLC and deserves to be studied more closely as both a single agent and in combination with other drugs to treat patients with SCLC.

Adult↗
PubMed1992

Endothelial function in thrombosis and thrombolysis.

The localization of tissue factor (TF) in atherosclerotic plaques of human aortas was immunohistochemically examined using rabbit anti-IgG against recombinant TF, which was expressed in E. coli. TF, the initiator of the extrinsic coagulation pathway, was ubiquitously present in atherosclerotic intima, and was expressed mainly by macrophages, but not by endothelial cells. It has been suggested that some macrophages in atherosclerotic intima co-express both molecules of TF and platelet-derived growth factor-B chain. We have developed a morphometrically quantitative in vitro assay for angiogenesis, using endothelial cultures on collagen gel incorporating plasminogen. With this method, we have obtained findings suggesting that plasminogen and plasminogen activators (PAs), especially urokinase-type PA (uPA) derived from endothelial cells, enhance angiogenic activity, probably by increasing endothelial migration. uPA was immunohistochemically observed to be primarily cell-associated on the focal contract areas, probably via its receptors on endothelial cells. These findings may support the hypothesis that the activation and regulation of the pericellular fibrinolysis system is closely related to angiogenesis.

Animals↗
PubMed1992

Increased hypothalamic somatostatin mRNA following dexamethasone administration in rats.

There is increasing evidence to suggest that supraphysiological doses of glucocorticoids suppress growth hormone secretion in vivo by augmenting somatostatin release from the hypothalamus; previously, we reported an increase in hypothalamic somatostatin content in dexamethasone-treated rats. To further examine whether the production of somatostatin really is augmented, hypothalamic somatostatin mRNA levels were determined by the Northern blot technique in female rats receiving 330 micrograms of dexamethasone daily for three days. In two series of experiments, hypothalamic somatostatin mRNA levels in dexamethasone-treated rats were significantly (p < 0.05) increased to 133 +/- 19 (mean +/- SD)% and 153 +/- 38% of the controls. In the dexamethasone-treated rats, plasma growth hormone levels were markedly suppressed compared with those of the controls. These results further support the hypothesis that pharmacological doses of glucocorticoids increase the production and release of somatostatin from the hypothalamus and thus inhibit growth hormone secretion, overriding the direct stimulatory effect of glucocorticoids on growth hormone production at the pituitary level.

Animals↗
PubMed1992

[A 4 degrees C-1 min method of cold water immersion test for peripheral circulatory function in fingers].

To assess the validity of a new simplified cold water immersion test (4 degrees C-1 min method) for peripheral circulatory function, comparison was made with the conventional method (10 degrees C-10 min method). These two different methods of cold immersion test were applied to 23 patients with vibration disease and 24 healthy men. Observation was made on finger skin temperature by a thermistor and complaints in the hand by a 5-step self-reported scale method every minute during the test. The patterns of recovery of skin temperature after cold immersion in each group were similar in both methods. Pain in the hand in the 4 degrees C-1 min method was less than that in the 10 degrees C-10 min method. The recovery rate at 5 min in the patients with Raynaud's phenomenon was lower than that in those without Raynaud's phenomenon in the 4 degrees C-1 min method (p < 0.01). However, no significant differences were noted in 10 degrees C-10 min method. The results suggest that the new method is feasible in detecting the response of vasodilation after immersion. In the recovery rate at 5 min after immersion, near values of the sensitivity and specificity were observed between 50% cut-off values in the 4 degrees C-1 min method and 30% value in the 10 degrees C-10 min method. Thus, the 4 degrees C-1 min method is considered to be more useful to evaluate the physiological response after cold immersion than the 10 degrees C-10 min method.

Adult↗
PubMed1992

[A thirteen-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T) in rats].

A 13-week oral repeated dose toxicity study of Suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 200, 600, 1800 and 5400 mg/kg/day using male and female rats. The results were as follows: 1. In general conditions, salivation were observed in some rats of both sexes given 1800 mg/kg/day. Both sexes given 5400 mg/kg/day disclosed salivation and soft stool and then died after showing ataxic gait, hyperesthesia and convulsion of legs. 2. Inhibition of body weight gain in both sexes given 5400 mg/kg/day were observed from the early stage of the treatment period. 3. The food consumption was decreased from about 3-week and the water consumption was increased from the initiation of study to about 3-week in both sexes given 5400 mg/kg/day. However, both of them were remarkably decreased prior to death. 4. Fecal examination for occult blood showed an increasing tendency in the incidence of positive findings in both sexes given 1800 mg/kg/day. 5. Hematological examination showed slight decreases in erythrocytic parameters in both sexes given 1800 mg/kg/day. In both sexes given 5400 mg/kg/day hemoconcentration was observed, some animals showing decreases in leucocyte and lymphocyte counts and lymphocyte percentage. 6. Biochemical examination showed increases in total and free cholesterol levels in males given 600 mg/kg/day or more, an increased cholinesterase and decreased levels of triglyceride and cholesterol ester ratio in males given 1800 mg/kg/day. An increase in LDH was observed in both sexes given 5400 mg/kg/day and half of these animals also showed increases in GOT and Urea N. 7. The absolute weights of the pituitary, brain, thymus, heart, lungs and kidneys were increased. However, no histopathological lesion was observed in these organs. As treatment-related histological changes, atrophy in the thymus and spleen, dilation in digestive tracts, neuronal necrosis and necrotic foci in the central nervous system, necrosis of lymphocytes in the lymphoid organs and a decrease in bone marrow cell were observed in both sexes given 5400 mg/kg/day. 8. After a 5-week recovery period, above-mentioned changes had disappeared. 9. From the above results, the non-effective dose level was estimated to be 200 mg/kg/day in males and 600 mg/kg/day in females, and toxic dose level 1800-5400 mg/kg/day in both sexes.

Administration, Oral↗
PubMed1992

Association of meningioma and ependymoma--case report.

We report the rare association of a meningioma and an ependymoma in a young boy. A meningioma was detected in the left cerebellopontine angle at age 8 months, and an ependymoma in the left frontal lobe 2 years later. Chromosomal analysis was normal, and his family showed no signs of phacomatosis. Both tumors were totally removed, and he recovered well after both operations.

Brain Neoplasms↗