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Biomedical subjects

K Enomoto

Publications and source records attributed to K Enomoto.

At least 145 records · Page 8Linked to original sources
PubMed1994

Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer.

The usefulness of CAF [cyclophosphamide (CPA)/doxorubicin (ADR)/5-fluorouracil (5-FU)] + medroxyprogesterone acetate (MPA) therapy for advanced/recurrent breast cancer was studied in a randomised trial at 56 institutions. Patients received CAF therapy [CPA: 100 mg, orally, days 1-14; ADR: 30 mg/m2, intravenously (i.v.), days 1 and 8; 5-FU: 500 mg/m2, i.v., days 1 and 8) in arm I, or CAF + MPA therapy (CAF + MPA 1200 mg, daily) in arm II. The response rate was significantly higher (P = 0.041) in arm II (53.5%, 46/86) than arm I (36.6%, 30/82). The response rate by tumour site was significantly higher for lymph node and bone lesions in arm II. Partial response duration and overall response duration were significantly longer in arm II. Incidences of anorexia and nausea/vomiting were significantly higher in arm I but in arm II, moon face, oedema and vaginal bleeding were significantly higher. Many patients in arm II demonstrated improvement in performance status and weight loss, suggesting a beneficial effect of MPA. The chemoendocrine therapy with CAF + MPA appears to be more beneficial than CAF alone in the treatment of advanced/recurrent breast cancer.

Administration, Oral↗
PubMed1994

Rapid purification of yeast cytoplasmic fumarate reductase by affinity chromatography on blue sepharose CL-6B.

The rapid and effective purification of soluble fumarate reductase from baker's yeast achieved by Blue Sepharose CL-6B chromatography. Cibacron Blue F3GA, the chromophore of Blue Sepharose, inhibited the activity of fumarate reductase. The enzyme bound to the column was selectively eluted by flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) or riboflavin. The purified enzyme was essentially homogeneous as indicated by polyacrylamide gel electrophoresis under nondenaturing conditions and under denaturing conditions in sodium dodecylsulfate. By this procedure, the enzyme could be rapidly purified with high yield from yeast cells.

Chromatography, Affinity↗
PubMed1994

Role of copper accumulation and metallothionein induction in spontaneous liver cancer development in LEC rats.

The LEC rat spontaneously develops liver cancer after suffering chronic liver injury caused by abnormal copper accumulation in the liver, but the role of copper accumulation in the induction of liver cancer remains obscure. We histochemically and biochemically examined the content of copper and metallothionein (MT), a cytoplasmic copper binding protein, in spontaneously developed preneoplastic and neoplastic liver lesions and compared them with those in the surrounding liver tissues. Histochemically, the majority of the preneoplastic liver lesions (68%) and liver cancers (59%) showed lower copper contents than the surrounding liver tissues and no lesions were shown to accumulate more copper than the surrounding tissues. A marked heterogeneity in copper staining was observed in cancer tissues. In contrast, these lesions showed an equal to higher MT content than their surroundings. Biochemical measurements of copper and MT in cancer tissues supported the histochemical findings. The bromodeoxyuridine (BrdU) labeling index was high in all cancer tissues and some of the preneoplastic liver lesions. Parts of the cancer tissues with negative or weak staining for copper were highly labeled with BrdU. Taking these results together, copper accumulation may exert a growth inhibitory effect on surrounding hepatocytes, whereas the hepatocytes in the liver lesions could proliferate, escaping from the effect of copper toxicity by increasing their MT induction and lowering copper accumulation. Thus, accumulation of copper may act as a promoting factor for the development of liver cancer in LEC rats by creating a selective growth environment.

Animals↗
PubMed1994

Contrasting effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on calcium transients in isolated rat cardiac myocytes.

OBJECTIVE: The aim was to examine the effects of an angiotensin converting enzyme (ACE) inhibitor and a calcium antagonist on intracellular calcium transients in isolated cardiac myocytes from a monocrotaline induced right ventricular hypertrophy model. METHODS: One week after monocrotaline injection, Sprague-Dawley rats were given either an ACE inhibitor (delapril-HCl) or a calcium antagonist (nilvadipine) for two weeks. Using fura-2/AM, calcium transients were measured in single myocytes separated from the right ventricle. RESULTS: The severe right ventricular hypertrophy observed in untreated rats was significantly reduced in drug treated animals. The inhibitory effects of delapril were more prominent than those of nilvadipine, although both drugs reduced right ventricular pressure to the same extent. Calcium transients in delapril treated rats were similar to those in control rats. On the other hand, the calcium transient in nilvadipine treated rats was decreased and its time course was prolonged. The changes were similar to those found in monocrotaline treated rats. The responsiveness of calcium transients to isoprenaline in delapril treated rats was similar to that in control rats. The responsiveness in nilvadipine treated rats was decreased, and was similar to that in monocrotaline treated rats. Delapril improved developed tension and the beta adrenoreceptor responsiveness of developed tension to isoprenaline. CONCLUSIONS: Although delapril and nilvadipine inhibited cardiac hypertrophy in monocrotaline treated rats, significant improvement of contractile function and beta adrenoreceptor responsiveness was observed only in the delapril treated rats. This improvement was partially due to the improvement in calcium transients and the restoration of the beta adrenoreceptor responsiveness of the calcium transient to beta adrenergic stimulation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Sequential decrease in tight junctions as revealed by 7H6 tight junction-associated protein during rat hepatocarcinogenesis.

A sequential decrease in the number of hepatocyte tight junctions during the course of rat hepatocarcinogenesis was demonstrated by immunohistochemistry with a new 7H6 monoclonal antibody generated in our laboratory. Semiquantitative analysis by confocal laser scanning microscopy revealed that the expression of 7H6 antigen was reduced in hyperplastic foci, hyperplastic nodules and hepatocellular carcinomas (HCC) to 43%, 28% and 25%, respectively, compared to corresponding normal liver tissues. 7H6 antigen was scarce in HCC with a trabecular pattern, whereas it was expressed intensely at the apical and basolateral membrane of HCC with a glandular pattern. Immunoblot analysis of 7H6 expression in hepatocellular carcinomas showed a decrease roughly coincident with that shown by immunohistochemistry. These results indicated, for the first time, that tight junctions decrease progressively during carcinogenesis, leading to disruption of cellular polarity and cellular adhesiveness.

Animals↗
PubMed1994

Contrasting effects of isoproterenol and phosphodiesterase III inhibitor on intracellular calcium transients in cardiac myocytes from failing hearts.

1. Effects of a newly developed phosphodiesterase (PDE) III inhibitor, E-1020, on intracellular calcium transients were compared with those of isoproterenol (ISO) in isolated single myocytes from failing hearts secondary to pulmonary hypertension induced by monocrotaline injection. Myocytes were isolated by enzyme digestion using a Langendorff apparatus. Changes in intracellular calcium concentrations ([Ca2+]i) were recorded using a fura-2 fluorescence microscopic technique. Cyclic AMP contents of the hearts were measured by radio-immunoassay. 2. Myocytes from failing hearts showed Ca2+ transients with a low peak (low amplitude) and delayed decline of Ca2+ transients. Both ISO and E-1020 increased peak [Ca2+]i, max + d[Ca2+]i/dt, and max - d[Ca2+]i/dt in a concentration-dependent manner while both agents decreased T80L (time to 80% decline of amplitude from peak light). The concentrations which increased peak [Ca2+]i by 50% were 1.6 x 10(-9) mol/L of ISO and 2 x 10(-6) mol/L of E-1020. These concentrations increased cAMP in the heart to the same levels. Analysis of the effects of both agents on peak [Ca2+]i versus max - d[Ca2+]i/dt showed that ISO is much more effective on peak [Ca2+]i while E-1020 is more effective on max - d[Ca2+]i/dt. 3. These results showed that the effects of ISO and E-1020 on the parameters of intracellular Ca2+ transients of single myocytes from failing hearts are slightly different, and suggest that E-1020 may improve diastolic function as well as systolic function in failing hearts.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Calcium transients in single myocytes and membranous ultrastructures during the development of cardiac hypertrophy and heart failure in rats.

1. We examined changes in intracellular calcium transients of separated single myocytes from the right ventricle (RV) of the rat heart during the change from adaptation to maladaptation in response to a pressure overload. 2. Right ventricular hypertrophy (RVH) secondary to pulmonary hypertension was induced by a subcutaneous injection of monocrotaline. Developed tensions of the RV-free wall were decreased as RVH progressed. Single myocytes were separated from the RV during different stages of RVH. Fura-2/AM-loaded cells were field stimulated, and changes in calcium transients were measured by Olympus OSP-3 system. We also examined membranous ultrastructures (sarcoplasmic reticulum, mitochondria, surface caveolae) involved in calcium metabolism in the hearts using scanning electron microscopy. 3. We observed characteristic changes in calcium transients during the change from adaptation to maladaptation, and also found that one parameter (amplitude) of calcium transients appeared to be correlated with the changes in the number of sarcoplasmic reticulum. 4. These results provided some insights into the mechanism of calcium handling of hypertrophied heart in response to a pressure overload from adaptation to maladaptation especially when stimulatory frequency was high, and suggested that heart rate control is a very important factor for the treatment of patients with congestive heart failure.

Animals↗
PubMed1994

Chemical modification of vesamicol binding sites and frequency augmentation-potentiation in neuromuscular transmission.

Vesamicol (AH5183), a potent and specific inhibitor of the vesicular acetylcholine uptake system, reduces at relatively high doses the slope of the log-linear frequency augmentation-potentiation (FAP) relation observed between the mean quantal content of endplate potential and the stimulation frequency. Recent biochemical studies identified two binding sites for vesamicol; one is the vesicular acetylcholine uptake system and the other is the vesamicol binding protein localized in the nerve terminal membrane. The present experiments were designed to determine the exact site of action of vesamicol on the FAP relation. Studies using epsilon-maleimidocaproic acid and picrylsulfonic acid, both membrane-impermeant protein-modifying reagents, revealed that these reagents diminished the vesamicol effect concomitant with an impairment of the functioning site for FAP. Because of the membrane-impermeant nature of the reagents, the present results were interpreted to mean that a vesamicol binding protein or a related component, localized in the nerve terminal membrane, is the target of action by vesamicol. This vesamicol binding component seems to play an important role in the stimulation frequency-dependent modulation of the evoked release of transmitter quanta observable as FAP.

Animals↗
PubMed1994

Analysis of intra- and intercellular calcium signaling in a mouse malignant glioma cell line.

Intra- and intercellular calcium signaling in glioma cells was examined by mechanical stimulation of a monolayer cell line of methylcholanthrene-induced mouse ependymoblastoma, 203-glioma, with a fine round-tip glass needle. A fura-2 fluorescence image of the glioma revealed a four- to eightfold increase in the cytosolic calcium ion concentration in directly stimulated signal cells. The increased calcium spread to surrounding cells at a speed of 20 microns/sec for a distance of up to 200 microns. Calcium was transmitted between adjacent cells and even in cells up to 200 microns distant from the initially stimulated cell. Microinjection of Lucifer yellow dye showed no gap junctional communication between cells. Depletion of extracellular calcium ion inhibited both cytosolic calcium elevation and propagation to neighboring cells by mechanical stimulus. An intracellular calcium blocker, TMB-8, eliminated the cytosolic calcium mobilization in a mechanically stimulated cell, but had no effect on calcium diffusion to surrounding cells. Nifedipine and verapamil, antagonists of voltage-dependent calcium channels, did not act on the mechanically induced calcium response. This suggests that some stimulating factor may trigger transmission of calcium, which may be ejected directly from single stimulated cells and mediated via a membrane receptor but not through a gap junction. The calcium signaling in a mechanically stimulated cell may be related to both an influx and a redistribution of intracellular calcium from internal stores, while calcium propagation to neighboring cells may involve calcium influx alone.

Animals↗
PubMed1994

[Abnormalities and clinical characteristics of growth factors and receptor systems in breast cancer].

Recent progress in molecular biology has revealed that the proliferation of breast cancer is controlled by various growth factors and their receptors. In particular, the amplifications and products of oncogenes which code growth factors and receptors can be different indicators of clinical malignancy from the conventional prognostic factors. We investigated the relation of c-erbB-2 and int-2 gene amplification, expression, ER and EGFR with clinical characteristics. In retrospective study, the cumulative 10-year survival rate of patients with c-erbB-2 and int-2 gene amplification was significantly lower than in patients without amplification. In 72 cases with tumor diameter less than 3.0 cm, which can be an indication of breast preservation surgery, the survival rates of patients in these gene amplified groups were significantly lower than in the non-amplified groups. As for prospective study, the results were the same as those from retrospective study. These data show that the cases with these gene amplification have a high biological malignancy and high risk of recurrence to distant organs, despite the small tumor diameter.

Breast Neoplasms↗
PubMed1994

[Late phase II clinical study of RP56976 (docetaxel) in patients with advanced/recurrent breast cancer].

A late phase II clinical study of RP56976 (Docetaxel), a new semisynthetic anticancer agent, was conducted in patients with advanced/recurrent breast cancer. RP56976 (Docetaxel) was in general administered at an intravenous dose of 60 mg/m2 with dose-free intervals of 3-4 weeks. Of the 74 patients enrolled, 64 patients completed the scheduled course of treatment. Three patients showed complete response (CR), 32 patients partial response (PR), 3 patients minor response (MR), 18 patients no change (NC), and 8 patients had progressive disease (PD). The overall response rate was 54.7%. The response rate in patients who previously had received chemotherapy was 55.7%, and the response rate in patients who had resistance to anthracycline agents or who did not respond to previous treatment was 58.7%. Adverse reactions included nausea/vomiting in 38 patients (57.6%), fatigue in 46 patients (69.7%), anorexia in 46 patients (69.7%), fever in 26 patients (39.4%), and alopecia in 60 patients (90.9%), all of which were tolerable. Abnormal laboratory findings included leukopenia (Grade III or more) in 57 patients (86.4%) and neutropenia (Grade III or more) in 56 patients (86.2%). The results show that RP56976 (Docetaxel) is an excellent agent with high antitumor effect for the treatment of advanced/recurrent breast cancer.

Adult↗
PubMed1994

[Analysis of glucose metabolism in patients with esophageal cancer by PET: estimation of hexokinase activity in the tumor and usefulness for clinical assessment using 18F-fluorodeoxyglucose].

We evaluated glucose metabolism of esophageal cancer by PET using 18F-fluorodeoxyglucose (FDG), in order to investigate its clinical usefulness. In 11 advanced cases k3 value reflecting hexokinase activity and Ci/Cp ratio expressing FDG uptake were calculated from radioactivity in the tumor (Ci) and the plasma (Cp). Both k3 and Ci/Cp were well correlated with hexokinase activity from the resected specimen, so Ci/Cp was considered to be a convenient index for clinical assessment of esophageal cancer. Forty-two cases before treatment revealed high accumulation of FDG, and 41 showed more than 2.0 of Ci/Cp. But, 10 normal controls and one esophageal benign tumor showed less than 2.0. As for 13 post-operative cases, 6 cases out of 7 with recurrence showed more than 2.0 for Ci/Cp, but all 6 cases of non-recurrent cases showed less than 2.0. FDG PET is an useful tool for differential diagnosis of recurrence. The clinicopathological findings were investigated in 26 resected cases. Age, location, vertical extension, histologic feature, lymph node metastasis and histologic stage were not correlative with Ci/Cp. As for DNA ploidy pattern, aneuploidy group showed significantly high Ci/Cp rather than diploidy group. Eight cases which showed more than 5.0 of Ci/Cp resulted in poor prognoses compared with 14 cases which showed less than 5.0.

Aged↗
PubMed1994

[Phase II study of CGS16949A, a new aromatase inhibitor--a dose finding study].

A dose finding phase II study of a novel aromatase inhibitor CGS16949A was performed in postmenopausal patients with advanced breast cancer. The daily dose of 1 mg (0.5 mg b.i.d.), 2 mg (1 mg b.i.d.) or 4 mg (2 mg b.i.d.) CGS16949A was administered orally for 8 weeks or more on dose escalation schedule. The response rates (CR+PR) in the evaluable cases were 13.6%, 22.0% and 13.3% in 1 mg/day group (1 mg group), 2 mg/day group (2 mg group) and 4 mg/day group (4 mg group), respectively. There was no statistically significant difference in the response rates among the three treatment groups. Median time to the onset of PR was 99, 113 and 114 days in 1 mg, 2 mg and 4 mg group, respectively, and the median duration of response was 276 days, 391 days and 277 days in 1 mg, 2 mg and 4 mg group, respectively. Five patients in each treatment group showed prolonged stabilization of disease ("long NC", lasting > or = 6 months). Median durations of stabilization were 223 and 241 days in 2 and 4 mg group respectively. The incidence of adverse effects were 11.9%, 7.5% and 13.0% in 1 mg, 2 mg and 4 mg group respectively, and 30 out of 33 symptoms (90.9%) were of mild. Laboratory abnormalities were observed in 12.2%, 22.9% and 23.8% in the respective groups of 1, 2 and 4 mg, and no patient experienced clinical symptoms related to these changes. Plasma estradiol concentration at one month after initiation of the treatment decreased significantly in comparison with pretreatment levels, and was slightly exceeding the limit of detection. Plasma cortisol was not changed. As shown in this results, CGS16949A showed sufficient efficacy and good tolerability in postmenopausal patients with advanced breast cancer. It was considered that the optimal dose in clinical use judged as 2 mg/day.

Administration, Oral↗
PubMed1994

[Clinical evaluation of CGS16949A in advanced or recurrent breast cancer--a multi-institutional late phase II clinical trial].

A multi-institutional late-phase II clinical trial of CGS 16949A was conducted at the dose of 1 mg twice daily in postmenopausal patients with advanced or recurrent breast cancer. Seventy patients entered into the study; 65 were eligible and 53 were complete cases. There were 3 CR, 11 PR, 10 long-NC, 14 NC and 25 PD with an overall response rate of 22.2% in 63 evaluable cases. The median period of overall duration of responses was 327.5 days. There were 22 cases that drug was found useful or better, and global usefulness rate was 33.8%. Forty six (76.7%) of patients experienced no side effects in this therapy. Grade 2 toxicities included anorexia (1 pt.), feeling of distension of abdomen (1 pt.), vomiting (1 pt.), fatigue (1 pt.), and only one patient experienced Grade 3 toxicity (anorexia). Grade 2 laboratory abnormalities were confirmed in two patients; one with elevated gamma-GTP and another with elevated LDH, and both were in the absence of liver metastasis. From these results, it is concluded that CGS16949A seemed to be a useful hormonal agent in the treatment of postmenopausal breast cancer.

Administration, Oral↗
PubMed1994

[Effects of nilvadipine on membrane potential in cultured neuroblastoma-glioma hybrid NG108-15 cells].

Examination was made of the effects of nilvadipine on membrane potential in cultured neuroblastoma-glioma hybrid NG108-15 cells using the current clamp method. The NG108-15 cells line differentiates into neuronal cells following the addition of 1mM dibutyryl cAMP to the culture medium. This agent (nilvadipine) was found to inhibit both sodium and calcium current on the cell membranes of differentiated NG108-15 cells. The inhibitory effect was reversible in a dose-dependent manner between 10 and 100 microM. A substantial washing-time with normal saline, over 20 minutes, was needed for complete recovery from inhibition. The higher the concentration of nilvadipine, the more suppressive was the action on the membrane potential. A higher dose of nilvadipine, 100 microM, caused the disappearance of the peak membrane potential. This effect appeared irreversible, when cells were incubated in the presence of 100 microM nilvadipine for a longer time. Nilvadipine may thus exert inhibitory effect on the electrophysiological activity of neuronal cells, especially the calcium current of the membrane.

Animals↗
PubMed1994

[Evaluation of clinical usefulness of 11C-methionine positron emission tomography (11C-MET-PET) as a tool for liver functional imaging].

We studied 11C-MET-PET in 17 clinical cases, 10 patients with obstructive jaundice and 7 normal volunteers, and analyzed its efficacy for the evaluation of hepatic functional reserve in major hepatectomy candidates. Differential absorption ratio (DAR) of 11C was compared to the hepatic protein synthesis rate (HPS), which is measured as the incorporation rate of 3H-labeled leucine in protein fraction, using needle biopsied liver specimen obtained from each hepatic segment. In the cases of normal liver function, DAR was well correlated with HPS. Also in jaundice cases with two exceptions, low HPS segment was demonstrated as low DAR segment. Consequently, MET-PET images could clearly provide functional liver imaging. After injection to 11C-MET, the increase in rate of radioactivity of 11C in plasma protein fraction was higher in jaundice cases than in normal volunteers, which is in accord with the results of our former study that cholestatic liver has accelerated protein synthesis rate. In summary, since 11C-MET-PET could demonstrate liver functional imaging, it might be a possible tool for liver function assessment in major hepatectomy candidates.

Carbon Radioisotopes↗