Biomedical subjects

S Nagao

Publications and source records attributed to S Nagao.

At least 163 records · Page 9Linked to original sources

PubMed1995

Determinants of drug response in camptothecin-11-resistant glioma cell lines.

Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent. Previous studies indicated that antitumor activity of CPT-11 was mediated through interaction of the drug with its target enzyme, DNA topoisomerase I (topo I). To elucidate the mechanisms of CPT-11 resistance, we have characterized glioma cell lines (T98G/CPT-11, C6/CPT-11) selected from the wild types (T98G. C6) for acquired resistance to CPT-11. T98G/CPT-11 and C6/CPT-11 cells demonstrated 5.4- and 7.3-fold increases, respectively, in resistance to CPT-11. Total glutathione S-transferase (GST) and GST-p activities were similar in CPT-11-sensitive and -resistant cells. No difference in intracellular accumulation of CPT-11 was observed between CPT-11-resistant and parental cells, indicating that an alteration in the uptake was not responsible for resistance. In addition, CPT-11-resistant cell lines showed no change in the total activity of Topo I, indicating an alteration in total Topo I was not responsible for resistance. In contrast, significantly increased intracellular glutathione (GSH) levels levels were found in T98G/CPT-11 and C6/CPT-11 cells (4.3- and 2.1-fold). Furthermore, Topo I samples from T98G/CPT-11 and C6/CPT-11 cells were at least 4- and 2-fold more resistant to the inhibitory effect of the CPT-11 on the relaxation activity of Topo I than were Topo I samples from their respective parent lines. The resistance of the enzyme itself to the effects of CPT-11 may be responsible for the resistance to CPT-11. Thus, at least two distinct mechanisms have been selected for the CPT-11-resistant cells.

Animals↗

PubMed1995

Intraoperative radiotherapy for gliomas.

Intraoperative radiotherapy (IORT) was performed in 20 of 36 patients with glioma; 11 glioblastomas, 7 malignant astrocytomas, 2 benign astrocytomas. Twenty or 25 Gy of irradiation was delivered in a single fraction intraoperatively, followed by external beam irradiation. The electron beam energy was selected so that the 80% isodose line fell at 2 or 3 cm below the residual tumor surface. Median survival time of IORT group was 14 months and that of the control group was 10 months. Difference of survival curve was significant. There were 6 incidences of complication caused by IORT; 1 radionecrosis, 1 convulsion, 1 abscess, and 3 severe brain edemas. IORT is suited for the treatment of malignant gliomas.

Adult↗

PubMed1995

A comparison of intraarterial carboplatin and ACNU for the treatment of gliomas.

BACKGROUND: Intraarterial chemotherapy with carboplatin for malignant gliomas has been tried recently, but its therapeutic efficacy and toxicity have not yet been elucidated. METHODS: We treated patients with malignant glioma by intraarterial chemotherapy using carboplatin, and compared the efficacy as well as the side effects with intraarterial ACNU. RESULTS: Twenty patients were treated with carboplatin (300 mg/m2) and 22 patients were treated with ACNU (80-200 mg/m2). Response (complete remission+partial response) rate for carboplatin was 12.5% compared to 45% for ACNU. Despite higher response rate for ACNU, the difference in the survival curves of the two groups was not significant. Three patients who were treated with high dose (150-200 mg/m2) of ACNU developed hemiparesis and aphasia. Seven patients treated with carboplatin developed 10 incidences of neurotoxicities; two hemiparesis, one aphasia, one blindness, one visual field disturbance, three convulsions, and two developed incidences of disturbances of consciousness. CONCLUSIONS: Intraarterial carboplatin was not superior to intraarterial ACNU in achieving remissions, and showed much greater tendency to produce neurotoxicities.

Adolescent↗

PubMed1995

Methylprednisolone retards the progression of inherited polycystic kidney disease in rodents.

Polycystic kidney disease in adult laboratory animals and humans is associated with enlarged kidneys and a progressive decline of renal function, resulting in death from uremia. Interstitial inflammation and fibrosis typically are observed in association with the development of renal insufficiency. To determine whether amelioration of interstitial inflammation and fibrosis may diminish cyst expansion/kidney enlargement and stabilize renal function, we administered methylprednisolone, an anti-inflammatory drug with antifibrogenic effects, to mice and rats with hereditary polycystic kidney disease. The experiment was repeated once for each species. Mice were studied both in America and in Japan. Weanling male and female mice (DBA/FG pcy/pcy [cystic] and +/+ [normal], n = 87 and 20, respectively) and rats (Han:SPRD Cy/+ and +/+, n = 70 and 33, respectively) were administered methylprednisolone (1 to 2 mg/kg/d) in the drinking water for 100 days (mice) or 42 days (rats). Control animals drank distilled water. In normal DBA +/+ mice, methylprednisolone had no effect on serum urea nitrogen (SUN) levels, kidney weight, or kidney/body weight. Untreated male and female mice developed cystic kidneys and azotemia to an equal extent. Methylprednisolone administered in America to mice with renal cystic disease decreased kidney weight, kidney/body weight, SUN levels, volume density of cysts, and severity of interstitial fibrosis. In Japan, methylprednisolone decreased kidney weight and SUN levels of animals with cystic disease, but the effect on kidney/body weight did not reach statistical significance. In contrast to mice, male rats developed more severe renal cystic changes and were more azotemic than female rats. Methylprednisolone administered to male rats with cystic disease decreased SUN levels, kidney weight, kidney/body weight, volume density of cysts, and severity of interstitial fibrosis. Methylprednisolone had no effect on kidney/body weight or SUN levels in female rats with renal cystic disease. In normal Han:SPRD (+/+) rats of both sexes, kidney and body weight were decreased by methylprednisolone, but kidney/body weight and SUN levels were unchanged. On the basis of this study, we conclude that methylprednisolone decreased the extent of renal enlargement, reduced renal interstitial fibrosis, and preserved kidney function in mice and rats with relatively severe forms of inherited polycystic kidney disease.

Animals↗

PubMed1995

Cyst fluid from a murine model of polycystic kidney disease stimulates fluid secretion, cyclic adenosine monophosphate accumulation, and cell proliferation by Madin-Darby canine kidney cells in vitro.

Cyst fluids from subjects with autosomal dominant polycystic kidney disease (ADPKD) cause polarized monolayers of MDCK cells to secrete fluid toward the apical compartment in vitro. To determine the extent to which secretagogue accumulation may be a general feature of polycystic diseases, cyst fluid from mice with a slowly progressive form of hereditary PKD (DBA/2FG-pcy/pcy) was added to polarized MDCK monolayers. Basolateral application of cyst fluids (diluted with culture medium to 15% final concentration) from 13 different animals 16 to 35 weeks old increased the fluid secretion rate from a baseline of 0.023 +/- 0.003 to 0.111 +/- 0.017 microL/cm2/h (P < 0.005). There was a direct relation between the concentration of cyst fluid and the rate of net fluid secretion. The secretory activity of cyst fluid was not altered by pronase treatment or boiling. Cyst fluid (10%) added to the basolateral surfaces of polarized MDCK monolayers for 24 hours increased cell cyclic adenosine monophosphate (AMP) levels from a baseline of 6.3 +/- 0.2 to 17.3 +/- 0.3 pmoles/monolayer (n = 3, P < 0.05). The capacity of cyst fluid to increase cyclic AMP levels was not changed by pronase treatment or boiling. There was a direct relation between the level of cellular cyclic AMP and the rate of transepithelial fluid secretion caused by cyst fluid. Cyst fluid increased thymidine incorporation by Madin-Darby canine kidney (MDCK) cells to an extent equal to that caused by epidermal growth factor and caused MDCK cells to form cysts in collagen matricies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Slow and macroscopic modulation of thermal fluctuations in myofibrils.

A comparison was made between fluctuations in a length of sarcomere from a myofibril during relaxed and rigor conditions. The fluctuations of the length associated with rigor states was due entirely to thermal fluctuations in the ambient. In contrast, the fluctuations associated with relaxed states were accompanied by extremely slow and macroscopically modulated thermal fluctuations. A slow, macroscopic modulation of the thermal fluctuations of the length of sarcomere was found to be unique to myofibrils in their relaxed conditions.

Animals↗

PubMed1995

Cell proliferation and advancement of hepatocarcinogenesis in the rat are associated with a decrease in connexin 32 expression.

The expression of connexin 32 (Cx32), a major liver gap junction protein, after partial hepatectomy (PH) and during development and progression of hepatocarcinogenesis was studied in the rat. Cx32 was quantitatively analyzed by counting immunohistochemically demonstrated protein spots on the membranes of hepatocytes. Livers were sequentially examined after PH to assess the correlation with cell proliferation. For the analysis of different stages in carcinogenesis, Cx32 was assayed in N-ethyl-N-hydroxyethylnitrosamine-induced enzyme altered foci (EAF), hyperplastic nodules (HN), hepatocellular carcinomas (HCC), pulmonary metastatic HCC and transplanted HCC in relation to their degree of altered enzyme expression. Cx32 showed: (i) a rapid decrease after PH to its lowest levels during and 12 h after the S phase of cell proliferation when 5-bromo-2'-deoxyuridine (BrdU) labeling indices were examined; (ii) a progressive decrease from early preneoplasia EAF to HN and HCC, values for pulmonary metastatic and transplanted HCC being 0; (iii) clearly inverse correlations with increased BrdU index and degree of altered enzyme expression in HN, indicating that these, with the lowest Cx32 count, are closest to HCC. Therefore, the observed decrease appears linked to cell proliferation and progression of hepatocarcinogenesis, providing a reflection of cellular independence and growth advantage.

Animals↗

PubMed1995

Endotoxin induces severe inflammatory reactions with necrosis at sites primed with delayed-type hypersensitivity reactions in guinea pigs.

Guinea pigs immunized with Freund's complete adjuvant received challenge injection of the purified protein derivative of Mycobacterium tuberculosis in the flanks and the corneas to prepare delayed-type hypersensitivity (DTH) reactions. The animals were injected subcutaneously with lipopolysaccharide (LPS) or a synthetic lipid A (LA-15-PP). At the skin site primed with DTH reaction, increased swelling and hemorrhagic reaction followed by a definite necrotic reaction occurred. Severe corneal reactions were also observed in the animals. These findings indicate that bacterial endotoxin modulates DTH reactions and induces severe inflammatory reactions.

Animals↗

PubMed1995

Modification of delayed-type hypersensitivity reactions by muramyldipeptide in guinea pigs.

N-Acetylmuramyl-L-alanyl-D-isoglutamine (muramyldipeptide, MDP) modulated delayed-type hypersensitivity (DTH) reactions and induced severe inflammatory lesions in guinea pigs. The animals immunized with heat-killed Mycobacterium tuberculosis were challenged with the purified protein derivative (PPD) at the flanks and the corneas to prepare DTH reactions at 2 weeks after the immunization, thereafter 24 h the animals received subcutaneous injections of MDP at the flanks of the opposite side. At the skin with the DTH reaction, increase of swelling and redness accompanied with hemorrhage and necrosis were observed. As corneal reactions in the animals that had received MDP, increase of cornea thickness, opaque and grayish-white and the projection of eyes accompanied with severe iritis were observed. Modification of the skin reaction occurred from 2 h after the MDP injection, rapidly increased to the maximum level around 10 h, maintained the level until 24 h, then slowly decreased. The polymorphonuclear leukocyte infiltration was observed from 15 min after the MDP injection, and tumour necrosis factor alpha, interleukin (IL)-1, and IL-6 levels in the serum and skin lesions increased after the MDP injection. Synthetic muramyltripeptide (N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-lysine) also provoked definite skin reactions, while the larger peptidoglycan fragments and various inflammatory agents including cytokines so far examined were inactive in this respect. Cortisone and heparin inhibited definitely and slightly the reaction, respectively. A comparison was made with the modified DTH reaction and the necrotic reactions which we reported previously.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1995

Morphological changes in human cerebral arteries after percutaneous transluminal angioplasty for vasospasm caused by subarachnoid hemorrhage.

Light and electron microscopy were used to study morphological changes in cerebral arteries after percutaneous transluminal angioplasty (PTA) for vasospasm in two patients with aneurysmal subarachnoid hemorrhage. One patient died of gastric bleeding 5 days after PTA. Postmortem examination of the inflated middle cerebral arteries revealed heterogeneously extended walls and dilated lumina. Throughout the vessel walls, the extracellular matrix, which was composed of nonmuscle components such as increased collagen, was stretched in conjunction with the medial muscle component. Also, torn and thinned areas of the wall and intramural hemorrhages were caused by overinflation. The second patient died of massive cerebral infarction caused by diffuse vasospasm 5 days after PTA. Prominent stretching of the walls at the atheromatous plaque margin in the dilated vessel was found in addition to the morphological changes observed in the first patient. These observations suggest that characteristic pathological alterations might be present in the vessel wall at the site of angioplasty. The major mechanism of the long-lasting effects of PTA seems to be the stretching and disruption of both the degenerative muscle and the proliferative nonmuscle components, mainly in the media of the vasospastic vessels.

Adult↗

PubMed1995

Growth, hemorrhage, and regression of multiple intracerebral vasoformative tumors: report of an unusual case.

A rare case of multiple hemorrhagic vascular tumors of the cerebrum and cerebellum is reported. Computed tomographic scans in a 16-year-old girl revealed multifocal brain lesions with "jewel ring"-like areas of contrast enhancement. An old hematoma cavity was found inside the surgical specimen. Histologically, it was a vascular tumor composed of anastomosing vascular channels with proliferating endothelial cells and hemorrhages at different stages. Upon further histopathological study, this lesion could not be classified as any known vascular tumor entity, although it resembled some vascular tumors, such as cavernous hemangioma and hemangioendothelioma. The patient received steroid and alpha interferon treatment. The lesions initially increased in number once, then resolved 10 months after onset. The neuroradiological and histopathological features in the present case were characteristic, and the clinical course was unusual.

Adolescent↗

PubMed1995

Abuse of smoking methamphetamine mixed with tobacco. III. Urinary metabolites of N-cyanomethylmethamphetamine, a pyrolysis product formed by smoking methamphetamine in tobacco, and species difference in its metabolism between rat and mouse.

1. N-cyanomethylmethamphetamine (CMMA) or methamphetamine (MA) was given intraperitoneally to rat and mouse (1, 3, 10 mg/kg). The basic urinary metabolites of CMMA were determined by mass spectrometry (MS) and compared with those of MA. 2. N-formylmethamphetamine (FMA), a specific metabolite of CMMA, was found in both rat and mouse urine. However, the dose percentage of FMA excreted in mouse urine was less than one-quarter of that in rat urine. 3. No CMMA was detected in rat or mouse urine collected within 72 h after dosing. All other basic metabolites of CMMA except FMA, i.e. MA, amphetamine (AP), p-hydroxymethamphetamine (OHMA) and p-hydroxyamphetamine (OHAP), were the same as those of MA in both species. 4. The excretion pattern of the urinary metabolites of CMMA was similar to that of MA except FMA in both species, though the amount of each metabolite of MA administration was larger than that of CMMA administration. However, in urinary excretion of FMA and hydroxylated metabolites, definite species differences were observed between rat and mouse. 5. A trace amount of FMA was identified in the urine of an abuser who had smoked MA with tobacco.

Amphetamines↗

PubMed1995

[Intratumoral pharmacokinetics following intraarterial administration of MCNU in patients with malignant gliomas].

This clinical study was undertaken to examine intratumoral (i.t.) pharmacokinetics after intraarterial (i.a.) administration of MCNU (80mg/m2) in 5 patients with glioblastoma (GB) and 2 with anaplastic astrocytoma (AA). After resection or stereotactic biopsy of the cystic lesion, an Ommaya reservoir was placed into the tumor cavity in all patients. The distribution of MCNU in blood was compatible with a two-compartment model, and the half life of the alpha-phase and beta-phase was 4.1 minutes and 160.4 minutes, respectively. MCNU was detected in the i.t. fluid in 5 cases, 4 of GB and 1 of AA. The concentration of i.t. MCNU gradually increased during the 5 to 30 minutes after i.a. injection to a level about 20.0% of its blood concentration. However, no MCNU was detected in patients showing partial response (3 of GB and 1 of AA) or no change (1 of GB) after the i.a. infusion of MCNU during maintenance chemotherapy. These results suggests that MCNU may transfer into the tumor tissues. Further investigation is warranted.

Adolescent↗

PubMed1995

[Relationship between cellular DNA contents and cell proliferation of non-small cell lung cancer estimated by simultaneous quantification of PCNA and DNA contents by flow cytometer].

Cellular DNA contents and proliferating cell nuclear antigen (PCNA) expression were studied in 273 fresh specimens from 65 surgically resected non-small cell lung cancers (adenocarcinoma 36, squamous cell carcinoma 29), and the relationship between the cellular DNA contents, especially the DNA ploidy pattern, and the cell proliferation was evaluated. The cellular DNA content and PCNA labeling index (LI) % were assayed with flow cytometry using simultaneous double staining technique. The cells of G0/G1 phase of cell cycle were classified into two categories by the DNA index (DI); diploid cells (DI = 1.0) and aneuploid cells (DI > 1.0). PCNA LI % was measured at all phase and G0/G1 phase of cell cycle. PCNA LI % of diploid tumors was significantly higher than that of normal lung tissues (p < 0.05), and PCNA LI % of aneuploid tumors was significantly higher than that of diploid tumors (p < 0.05). PCNA LI % of diploid cells of tumors was significantly higher than that of diploid cells of normal lung tissues (p < 0.05), and PCNA LI % of aneuploid cells of tumors was significantly higher than that of diploid cells of tumors (p < 0.05). In adenocarcinomas, % aneuploid was directly correlated to PCNA LI % at all phase. From this result, it was concluded that DNA aneuploid tumors have a high cell proliferative pattern when the % aneuploid is high in DNA histogram.

Adenocarcinoma↗

PubMed1995

[A case of accessory nerve neurinoma presenting an intracisternal tumor].

A case of neurinoma from the spinal accessory nerve which is located in the cisterna magna is reported. A 54-year-old woman was admitted to the institute in 1990 with complaints of headache, nausea and ataxic gait for several months. Plain CT showed dilation of the lateral ventricles and a mass of lower density in the cisterna magna. The capsule and septa of the mass were enhanced with contrast medium. MRI showed the mass was low intense on T1-weighted images and high intense on T2-weighted images. Gadolinium visualized the mass multicystic. V-P shunt was performed before tumor resection. Through suboccipital craniectomy and C1 laminectomy the tumor was removed. The tumor had a long neck attached to the right spinal accessory nerve and extended to the cisterna magna.

Accessory Nerve↗

PubMed1995

[The efficacy of granisetron as a prophylactic anti-emetic agent used in conjunction with MCNU and VP16 chemotherapeutic regimens in the management of a pediatric case of hypothalamic anaplastic astrocytoma].

The management of a 12-year-old boy with hypothalamic anaplastic astrocytoma is reported herein. The pediatric patient underwent a subtotal removal of his brain tumor, and subsequently received multimodal treatment comprising radiotherapy (30.6 Gy to the whole brain and 50.4 Gy to the local lesion) and immunochemotherapy with MCNU (80 mg/m2, day 1), VP 16 (50 mg/day, days 2 to 6), and interferon-beta (3 x 10(6) units/day, initiating on day 2 for 4 weeks). The immunochemotherapy was given as of 4 weeks after radiotherapy. The administration of anti-cancer drugs caused severe nausea and vomiting, the intra-carotid infusion of MCNU being particularly emetogenic. The multi-modal treatment was then discontinued for a few weeks. A partial response was obtained, and the patient subsequently received 3 courses of maintenance therapy at six-month intervals using the same protocol as for the initial immunochemotherapy. During maintenance therapy, granisetron (40 micrograms/kg) was given intravenously 30 minutes before and one day after the injection of MCNU. Owing to the anti-emetic management of this patient, there were no complications throughout the chemotherapy. The patient has now survived for more than 3 years with a good quality of life, showing a Karnofsky performance score of 90.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Effect of lipopolysaccharide on thymidine salvage as related to macrophage activation.

Lipopolysaccharide (LPS), known as one of the potent activators of macrophages, has inhibitory effects on the proliferation of normal macrophages and macrophage-like cell lines. We report here that LPS dose- and time-dependently suppressed the tritiated thymidine ([3H]TdR) incorporation into the acid-insoluble fraction with a significant inverse correlation to the tumour necrosis factor-alpha (TNF) production in the J774.1 macrophage cell line. Among the three tested enzymes involved in DNA synthesis, only thymidine kinase (TK) activity decreased progressively in parallel with the decline in [3H]TdR incorporation, reaching 97% inhibition within 12 hr of LPS treatment, while changes in the activities of other two enzymes, DNA polymerase alpha and thymidylate synthase (TS), were less significant. On the other hand, LPS inhibited the cell proliferation only incompletely, as judged by 62% inhibition of cell growth at 36 hr. Even in the experiments done in a TdR-free medium, cell growth was inhibited by LPS to the same extent, suggesting that TK was not directly involved in the proliferation of J774 cells. LPS also inhibited the conversion of TdR to thymidine monophosphate (TMP) in murine peritoneal exudate macrophages (PEM). Thus LPS-induced suppression of TdR salvage related to TNF production is common in both normal and neoplastic macrophages, and therefore may be of potential importance in the process of macrophage activation.

Animals↗

PubMed1994

Distinct kinetics of subunit autolysis in mammalian m-calpain activation.

Subunit autolysis of mammalian m-calpain upon activation was examined in kinetic terms using a set of antibodies recognizing different portions of the protease. Activation of m-calpain by calcium resulted in no apparent autolysis in the large catalytic subunit, whereas the small regulatory subunit underwent immediate autolysis followed by substrate proteolysis. This profile of subunit autolysis is distinct from that of the other ubiquitous isozyme, mu-calpain, in which autolysis of the large subunit and then of the small subunit precedes substrate proteolysis under the normal conditions. The activation state of m-calpain thus is not reflected by the large subunit autolysis. The mode and role of autolysis may vary among calpain isozymes.

Amino Acid Sequence↗