Increased serum level of vascular endothelial growth factor in Crow-Fukase syndrome.
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Biomarkers↗
Biomedical subjects
M Kuroda
Publications and source records attributed to M Kuroda.
Evaluation of organic solvent ototoxicity by the upper limit of hearing.
To clarify the effects of organic solvents on hearing, we measured the upper limit of hearing in 93 male workers exposed to organic solvents in 7 factories that produced plastic buttons or baths. Medical examinations, environmental monitoring (i.e., concentration in breathing-zone air), and biological monitoring (i.e., concentration in urine) of the organic solvents were also done. Although the organic solvent concentrations in the environmental monitoring were lower than the occupational exposure limit, the upper limit of hearing was reduced in workers who were exposed for 5 y or more. This reduction was dose-dependent and was related to styrene concentrations in breathing-zone air and mandelic acid concentrations in urine. Even individuals who had normal medical examinations showed a reduced upper limit of hearing. The upper limit of hearing may serve as an early detection indicator of health effects in workers constantly exposed to styrene.
Acetone↗
Effects of PKC inhibitors on suppression of thermotolerance development in tsAF8 cells.
Effects of protein kinase C (PKC) inhibitors (H7, staurosporine, calphostin C) on thermotolerance development were investigated in temperature sensitive tsAF8 cells derived from Syrian hamster BHK21 cells. Cells were pre-heated at 45 degrees C for 20 min, incubated at 34 degrees C with PKC inhibitors for varying lengths of time, i.e. 1.25-10.0 h, and then heated at 45 degrees C for 30 min. Increasing survival fractions after the second heat treatment was inhibited by the treatment with H7 (40-160 microM), with staurosporine (0.05-1.0 microM), and with calphostin C (0.8, 1.2 microM) in a concentration dependent manner. When the concentrations of these PKC inhibitors were low, the restraint of increasing survival fractions was temporary, since survival fractions increased 3-7.5 h after pre-heating. However, the survival fractions were almost constant by the treatment with 160 microM H7 and 1.0 microM staurosporine. Induction of HSP72 after heat stress was investigated in tsAF8 and BHK21 cells. Cells were heated at 45 degrees C for 20 min and incubated at 34 or 39.7 degrees C (tsAF8), at 37 degrees C (BHK21). Intensity of intracellular fluorescence from HSP72 was measured by flow cytometry. HSP72 was induced in BHK21 cells, but there was no definite induction of HSP72 in tsAF8 cells at either 39.7 or 34 degrees C. These results suggest that PKC is related with the thermotolerance development in tsAF8 cells; however, HSP72 is not involved in the thermotolerance development in tsAF8 cells.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Inhibition of thermotolerance observed on tsAF8 cells.
The characteristic development of thermotolerance was examined in tsAF8 cells, which were temperature sensitive cell line derived from BHK21. tsAF8 cells lose RNA polymerase II activity and arrest in the G1 phase of the cell cycle at the nonpermissive temperature of 39.5-40.6 degrees C. tsAF8 cells were pre-heated at 45 degrees C for 20 min, incubated at 34 or 39.7 degrees C for different durations, and then heated again at 45 degrees C for 30 min. The cells were trypsinized immediately after the second heating to evaluate cell survival. As a result, thermotolerance was developed rapidly in the cells incubated at 34 degrees C. However, the survival rate of the cells incubated at 39.7 degrees C was almost constant. Thermotolerance of BHK21 cells, which were wild-type cells of tsAF8 cells, developed at 39.7 degrees C. These results suggest that thermotolerance may be inhibited in tsAF8 cells incubated at 39.7 degrees C, and that some metabolism which is inhibited in tsAF8 cells at 39.7 degrees C may be related to thermotolerance development.
Animals↗
The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours.
It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3), a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5 degrees C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.
Animals↗
For the clinical application of thermochemotherapy given at mild temperatures.
It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43 degrees C. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0 degrees C. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue.
Animals↗
Age variation in the upper limit of hearing and amplitude of eye accommodation in childhood and adolescence.
The upper limit of hearing and amplitude of eye accommodation were examined, and their standard aging curves were established in order to evaluate their age-related changes in childhood and adolescence. The subjects were 2497 audiometrically and otologically normal ears and 2349 optometrically and ophthalmologically normal eyes ranging in age from 5 to 24 years in Japan. The upper limit of hearing was measured by the equipment made by us. The amplitude of eye accommodation was calculated at near point and far point measured by the ophthalmodynamometer. Both the upper limit of hearing and amplitude of eye accommodation became gradually less as age increased. The variability of the upper limit of hearing was less than that of the amplitude of eye accommodation. Standard aging curves were established in childhood and adolescence by calculating 10th, 25th, 50th, 75th and 90th centiles. There is no significant relationship between the upper limit of hearing and the amplitude of eye accommodation.
Accommodation, Ocular↗
Uterine cirsoid aneurysm: MRI and MRA.
Uterine cirsoid aneurysm is uncommon. It is important to make a diagnosis of this disease preoperatively, because repeated curettages may induce life-threatening massive genital bleeding. We present a case of a 51-year-old woman with uterine cirsoid aneurysm in whom MRI and MRA were very useful for the preoperative diagnosis. The radiologic appearances on ultrasonography, CT, conventional SE MRI, MRA, dynamic MRI, and pelvic angiography are presented. Conventional SE T1-weighted and T2-weighted images demonstrated multiple flow voids in the uterus and bilateral adnexal regions. MRA demonstrated a cluster of distinct, tortuous, and coiled vascular channels in the pelvis. MRA could obtain images almost equal to angiography and was considered to be an excellent noninvasive imaging technique for the diagnosis of uterine cirsoid aneurysm.
Aneurysm↗
Endometrial carcinoma: dynamic MRI with turbo-FLASH technique.
PURPOSE: Our goal was to investigate the usefulness of dynamic MRI with the turbo-FLASH technique in estimating myometrial invasion by endometrial carcinoma. METHOD: Forty-six patients with endometrial carcinomas were evaluated with pathologic correlation. Dynamic MRI was performed with the rapid administration of Gd-DTPA using the turbo-FLASH technique. RESULTS: The inner muscle layer showed more rapid contrast enhancement effects than the outer muscle layer even after menopause. Contrast-to-noise ratio between the inner muscle layer and endometrial carcinoma was maximum at approximately 50 s after administration of Gd-DTPA. In postmenopausal women, the accuracy in estimating myometrial invasion with T2-weighted images, contrast-enhanced T1-weighted images, and dynamic MRI was 66.7, 77.8, and 92.6%, respectively. CONCLUSION: Dynamic MRI with the turbo-FLASH technique is considered to be a useful imaging method for the estimation of myometrial invasion by endometrial carcinoma, especially in postmenopausal patients.
Adult↗
Vestibular findings and brainstem pathology in two siblings with Cockayne's syndrome.
Two siblings with Cockayne's syndrome (CS) are described. Both showed cachectic dwarfism, photosensitivity and progressive neurological dysfunction. The damped-rotation test revealed no vestibular nystagmus in one of them, and reduced per-rotatory nystagmus in the other. Neuropathological examination in the former subject disclosed neuronal loss with fibrillary gliosis in the vestibular nuclei, whereas neuronal degeneration was not apparent in the abducens nuclei, the oculomotor nuclei and the paramedian pontine reticular formation. Our findings suggest that CS might cause vestibular dysfunction as well as hearing loss and that the lesions in the vestibular nuclei might be related to the vestibular dysfunction.
Adolescent↗
Effects of hyperthermia and cepharanthin on adriamycin accumulation with changes in extracellular pH.
We compared adriamycin (ADR) accumulation with the intensity of intracellular fluorescence of 3,3'-(di-n-hexyl)-2,2'-oxacarbocyanine iodide (NK-2280), an indicator of cell membrane potential, after hyperthermia and examined the effects of cepharanthin (CEP) on the accumulation of ADR and NK-2280 in wild and ADR-resistant strains of Ehrlich ascites tumour (EAT) cells. Among wild 0.2 and 1-microgram ADR-resistant strains of EAT cells, intracellular accumulation of both ADR and NK-2280 decreased with an increase of ADR resistance. Hyperthermia at 42 degrees C and CEP induced a marked increase in accumulation of both ADR and NK-2280 in the ADR-resistant strains of EAT cells. The increase in ADR accumulation by hyperthermia and CEP is possibly due to an increase in the cell membrane potential and the inhibition of ADR efflux by CEP respectively. In the wild strain of EAT cells, we also evaluated the effect of extracellular pH change on ADR accumulation and the cell membrane potential and their alteration by hyperthermia and CEP. ADR accumulation decreased as pH decreased, but the cell membrane potential was not appreciably affected by pH change so far examined. Hyperthermia alone or combined with CEP significantly increased ADR accumulation in a pH range from 6.2 to 7.6. Hyperthermia increased the accumulation of ADR in the tumour cells, although its pH dependency was not completely resolved. CEP enhanced ADR accumulation more markedly in ADR-resistant cells than in wild-type cells. Therefore, the combination of hyperthermia and CEP may be very effective to increase the ADR cytotoxicity to ADR-resistant tumours.
Alkaloids↗
Thermal enhancement of the effect of ifosfamide against a spontaneous murine fibrosarcoma, FSa-II.
The effect of hyperthermia on the cytotoxicity of 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-,1,3, 2-oxazaphosphorine-2-oxide, ifosfamide (IFO) was investigated in vivo. Tumours were early generation isotransplants of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. The tumour cell suspensions containing approximately 2 x 10(5) cells were transplanted into the dorsal site of the C3Hf/Sed mouse foot. Hyperthermia was given by immersing the tumour-bearing foot into a constant temperature water bath set at 41.5 degrees C for 0-90 min when tumours reached 34 mm3. IFO was administered i.p. immediately before hyperthermia. Tumour response was studied by the tumour growth (TG) time assay; namely, the TG time or the time for one-half of the treated tumours to reach 700 mm3 from the initial treatment day was determined and the dose-response curves was fitted between the TG time and IFO dose. The anti-tumour effect of IFO was enhanced at this elevated temperature. The thermal enhancement ratio (TER) or the ratio of the slope of dose-response curve at 41.5 degrees C to that of dose-response curve without hyperthermia was relatively small for a short treatment time of 30 min. This TER was smaller for IFO than the TERs for cyclophosphamide (CY) and BCNU which had been studied in our laboratory. However, the TER for IFO increased greatly with a prolongation of treatment time from 30 to 90 min, and exceeded the TER for CY. The TERs were 1.5, 2.6 and 3.6 for heating time of 30, 60, and 90 min, respectively, indicating that a long treatment time such as 90 min at moderately elevated temperatures could result in a substantial enhancement of the antitumour effect of IFO.
Animals↗
Influence of metabolic inhibitors on the intracellular accumulation and retention of adriamycin.
We observed modulation of the intracellular accumulation and retention of adriamycin (ADR) by metabolic inhibitors in Ehrlich ascites tumor cells (wild type EAT cells) and their ADR-resistant EAT strain. In the wild type EAT cells, ADR accumulation was increased by 0.2 mM of 2,4-dinitrophenol (2,4-DNP), 1 mM of sodium azide (NaN3) or 1 mM of potassium cyanide (KCN), which were the metabolic inhibitors, and its efflux wa inhibited by the metabolic inhibitors several fold. These results indicate that in wild type EAT cells. one of the mechanisms which increase the intracellular accumulation of ADR involve inhibition of efflux, which may be inhibited by these metabolic inhibitors. In ADR-resistant EAT strain, 2,4-DNP or KCN increased the ADR accumulation, but NaN3 did not affect it. Further, ADR efflux in the ADR-resistant cells after incubation with the metabolic inhibitors were similar to that found in the control. This indicates that in the ADR-resistant cells, NaN3 does not affect ADR accumulation and retention, and that the increase in the ADR accumulation by KCN and 2,4-DNP was considered to be due to the influx rather than efflux. In addition, 2,4-DNP, NaN3 or KCN inhibited ADR efflux in the wild type EAT cells but not in the ADR-resistant EAT strain. This suggests that there is an efflux mechanism in the ADR-resistant EAT strain that involves an energy system that differs from the energy system in wild type EAT cells or does not depend on energy produced by the metabolic inhibitors.
2,4-Dinitrophenol↗
Intracellular accumulation and retention of calcein in Ehrlich ascites tumor cells and their adriamycin-resistant strain.
In this study, we observed the intracellular accumulation and retention of calcein in Ehrlich ascites tumor cells (wild type EAT cells) and their adriamycin (ADR)-resistant strain to further study the mechanisms of ADR accumulation. In the wild type EAT cells, intracellular accumulation of calcein increased rapidly, but it was not incorporated into the cells in the ADR-resistant strain. This suggests that the efflux system or the inhibition system of influx, which does not exist in the wild type EAT cells, involves in the ADR-resistant strain. Calcein incorporated into the cells was effluxed from the cells in both strains at almost the same rate. This suggests that the both strains may use a similar efflux system against calcein. P-gp extrudes calcein-AM directly from the cell membrane, but not calcein. Calcein is effluxed by multidrug resistant protein (MRP) or multi-specific organic anion transporter (MOAT). Therefore, the mechanism, which extrudes calcein of both strains, may be the other efflux system included MRP or MOAT apart from P-gp. In the same medium condition as treating in the calcein efflux experiments, about 20% amount of ADR incorporated into the cells was effluxed in the ADR-resistant cells, but not in the wild type cells. Since the efflux rates in the ADR differed from those in calcein in the same medium condition, the mechanism of the ADR efflux might differ from that of calcein efflux in the ADR-resistant strain.
Animals↗
Overexpression of manganese superoxide dismutase gene suppresses spontaneous apoptosis without a resultant alteration in in vivo growth of the mouse fibrosarcoma, FSa-II.
The relationship between spontaneous apoptosis and overexpression of manganese superoxide dismutase (MnSOD) gene was examined in vivo. The mouse fibrosarcoma cells expressing high MnSOD activities due to transfection with the human MnSOD cDNA (SOD-H), or the fibrosarcoma cells transfected with the selectable marker alone (NEO), were transplanted into immune-deficient Fox Chase SCID C.B-17/Icr-scid Jcl mice. Apoptosis in tumors was visually quantified by the in situ end-labeling method. The number of apoptotic cells in the SOD-H tumors was significantly less than that in the NEO tumors. The tumor growth time of the SOD-H tumors to grow from 34 to 500 mm3 in one-half of the mice was slightly longer than that of the NEO tumors, but the difference was not statistically significant. These results suggest that overexpression of MnSOD gene is involved in the suppression of spontaneous apoptosis, without a resultant alteration in the tumor growth.
Animals↗
Influence of bovine calf serum on the intracellular accumulation and retention of adriamycin.
In this study, we observed the influence of bovine calf serum (BCS) on the intracellular accumulation of adriamycin (ADR) in Ehrlich ascites tumor cells (wild type EAT cells) and their ADR-resistant strain. The ADR accumulation treated in the medium not containing BCS was 3-fold of that containing 10% BCS. ADR incorporated into cells was not effluxed in the absence of the BCS, while it was rapidly effluxed for 30 minutes to about 20% of the amount incorporated into the cells in the presence of 10% BCS in both strains. This suggests that BCS remarkably decreases the ADR accumulation due to the promotion of ADR efflux. Further, the ADR accumulation decreased with increasing concentrations of BCS in both strains. This indicates that BCS promotes the ADR efflux, depending on its concentrations. BCS was heated at 100 degrees C for 7 minutes and its protein contents were degenerated. Its influence in the ADR accumulation of wild type and ADR-resistant strain was apparent. The ADR accumulation decreased with increasing concentrations of heated BCS in both strains, as well as in the untreated BCS. Thus, the protein content of the BCS did not affect ADR accumulation. Therefore, it is necessary to investigate which components of BCS affect the promotion of ADR efflux.
Animals↗
Effects of quercetin on the cell growth and the intracellular accumulation and retention of adriamycin.
In this study, we examined the inhibitory effects on cell growth and the effects of quercetin on intracellular accumulation of adriamycin (ADR) in wild type Ehrlich ascites tumor cells (wild EAT cells) and their ADR-resistant strain. Quercetin strongly inhibited growth in both strains. Cell growth reached a plateau at 3.5 days in the wild type EAT cells and at 7 days in the ADR-resistant strain. The inhibitory concentration in 50% of the ADR-resistant cells on day 7 (24 microM) was twice that of the wild type EAT cells on day 4 (12 microM) after continuous treatment with quercetin. Quercetin decreased the ADR accumulation in the wild type cells but did not affect it in the ADR-resistant cells. Further, quercetin did not affect the retention of ADR in either strain. These results indicated that quercetin decreased ADR accumulation without extruding ADR in the wild type EAT cells. ADR accumulation in the ADR-resistant cells treated with quercetin for 7 days was increased with increasing concentrations of quercetin. Moreover, ADR accumulation in the ADR-resistant cells treated with 50 microM quercetin for 7 days, increased to 186.6% and to 181.9% of that in untreated cells after 60 minutes and 120 minutes incubation, respectively, whilst it increased to 70% from 37.5% of that in the wild type EAT cells after 60 minutes incubation. These findings indicated that quercetin might reverse ADR-resistance.
Animals↗
Influence of the extracellular pH, an inhibitor of Na+/H+ exchanger and an inhibitor of Cl-/HCO3-exchanger on adriamycin accumulation.
We examined the influence of the extracellular pH, an inhibitor of Na+/H+ exchanger: 3,5-diamino-6-chloro-N-(diaminomethylene) pyrazinecarboxamide (amiloride), and an inhibitor of Cl-/HCO3-: 4,4 -diisothiocyanatostilbene -2,2 -disulfonic acid (DIDS) on the accumulation of adriamycin (ADR) in Ehrlich ascites tumor cells and their adriamycin-resistant strain. A good correlation between the increases in ADR accumulation and the extracellular pH was shown in the both strains. The ADR accumulation decreased with an increasing concentration of amiloride or DIDS in both strains. These findings demonstrate that the influx of ADR was related closely to the efflux of H+ or to the activities of Na+/H+ ex-changer and Cl-/HCO3-exchanger. Therefore, raising the extracellular pH and enhancement of the activities of either Na+/H+ exchanger or Cl-/HCO3-exchanger may result in the potentiation of the cytotoxic effect of ADR through increase of ADR influx.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗