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S Masunaga

Publications and source records attributed to S Masunaga.

At least 55 records · Page 3Linked to original sources

Effects of boron neutron capture therapy using borocaptate sodium in combination with a tumor-selective vasoactive agent in mice.

Boron neutron capture therapy (BNCT) destroys tumor cells by means of alpha particles and recoil protons emitted by 10B(n, alpha)7Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of 10B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of 10B-enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of 10B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The 10B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor 10B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7- to 2.7-fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, 10B concentrations 2.1- to 6.9-fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor 10B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on 10B levels at the time of irradiation. Because 10B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15-180 min after FAA + BSH, or in those in skin irradiated at 120 and 180 min.

Animals↗

Applicability of combination with tirapazamine in boron neutron capture therapy.

SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating cells. After injection of tirapazamine (TPZ), a bioreductive agent, combined with sodium borocaptate-10B (BSH) or dl-p-boronophenylalanine-10B (BPA) administration, the tumors were irradiated with thermal neutrons, and then isolated and incubated with cytochalasin-B (a cytokinesis blocker). The micronucleus (MN) frequency in cells without BrdU labeling (quiescent (Q) cells) was determined by means of immunofluorescence staining for BrdU, and that for total cells was obtained from tumors not pretreated with BrdU. Even when no 10B-compound was administered, TPZ increased the MN frequency of tumor cells including Q cells, resulting in reduction of the difference in MN frequency between total and Q cells, mainly by increasing the MN frequency of Q cells. TPZ increased the MN frequency of Q cells when combined with BPA administration, but TPZ showed no apparent effect on each cell population when combined with BSH. Namely, TPZ reduced the difference in MN frequency between total and Q cells caused by 10B-compound administration, especially when BPA was administered. From the viewpoint of the overall cell killing effect in boron neutron capture therapy (BNCT), combination with TPZ appeared to be useful in BPA-BNCT, but not in BSH-BNCT.

Animals↗

[Detection of apolipoproteins E5 and E7 by a widely used commercial ApoE IFE kit--evidence provided by genotyping].

The purpose of this study is to examine a possibility to detect apolipoprotein (apo) E5 and E7 isoproteins with a commercial kit widely used (Phenotyping Apo E IFE System, Jokoh Co. LTD., Tokyo) and to clarify the frequency of the rare alleles in Central Japan. A total of 1,445 subjects living in Central Japan (1,030 hemodialysis patients and 415 apparently healthy individuals) was phenotyped for apo E isoproteins with the kit using isoelectric focusing with immunoblotting. In 23 subjects, unique apo E4 isoproteins, which migrate more basically than apo E4 isoprotein, were found. These unique isoproteins were proved to be apo E5 or E7 isoproteins by PCR with restriction fragment length polymorphism and with amplification refractory mutation systems, respectively. No significant differences in the frequencies of apo E5 or apo E7 alleles were observed between healthy individuals and hemodialysis patients (0.011 vs. 0.018, NS). The frequencies of apo E5 and E7 alleles were 0.001 and 0.005, respectively, in healthy individuals, and 0.003 and 0.005, respectively, in hemodialysis patients. These data in Central Japan were consistent with those in Western Japan (Matsunaga, et al, Clin Genet, 1995). These results indicate that the commercial kit is applicable to detect the rare alleles, apo E5 and E7 alleles and that the frequencies of the rare alleles in Central Japan are similar to those in Western Japan.

Adult↗

Mutagenic effects at HPRT locus induced in Chinese hamster ovary cells by thermal neutrons with or without boron compound.

CHO cells were exposed to thermal neutrons and their mutation frequency was determined. The Kyoto University Research Reactor (KUR), which has a very low level of contamination by gamma-rays and fast neutrons was used as a thermal neutron source. Cells were irradiated in the presence or absence of boric acid to determine mutation frequency and cell survival. Thermal neutron irradiation was 2.5 times as mutagenic as gamma-irradiation without boron. In the presence of boron, however, thermal neutron irradiation was from 4.2 to 4.5 times as mutagenic as gamma-irradiation. When the mutation frequency was plotted against the survival fraction, a higher degree of mutagenicity was observed in the presence than in the absence of boron. These results suggest that the enhancement of thermal neutron-induced mutation with boron is strongly associated with alpha-particles released by 10B(n, alpha)7 Li reaction.

Animals↗

Clinical results of radiofrequency hyperthermia for malignant liver tumors.

PURPOSE: To evaluate thermometry and the clinical results of radiofrequency (RF) hyperthermia for advanced malignant liver tumors. METHODS AND MATERIALS: One hundred seventy-three patients with malignant liver tumors treated between 1983 and 1995 underwent hyperthermia. The 173 tumors consisted of 114 hepatocellular carcinomas (HCCs) and 59 non-HCCs (47 metastatic liver tumors and 12 cholangiocarcinomas). Eight-megahertz RF capacitive heating equipment was used for the hyperthermia. Two opposing 25-cm electrodes were generally used for heating the liver tumors. Our standard protocol was to administer hyperthermia 40-50 min twice a week for a total of eight sessions. The liver tumor temperature was measured by microthermocouples when possible. Transcatheter arterial embolization, radiotherapy, immunotherapy, and chemotherapy were combined with hyperthermia treatment in accordance with each patient's liver function. RESULTS: One hundred forty (81%) of the 173 patients who underwent more than four sessions of hyperthermia were evaluated in this study. Thermometry was performed in 77 (55%) of these 140 patients. The maximum tumor temperature, average tumor temperature, and minimum tumor temperature in the HCC were (mean +/- standard error) 41.2 +/- 0.2 degrees C, 40.3 +/- 1.3 degrees C, and 40.1 +/- 0.2 degrees C, respectively. The same thermometry results for non-HCC were 42.3 +/- 0.2 degrees C, 41.2 +/- 0.2 degrees C, and 40.9 +/- 0.2 degrees C, respectively. The maximum and minimum temperatures (41.8 +/- 0.2 degrees C and 40.3 +/- 0.4 degrees C) in the patients with a complete or partial response (CR or PR) were higher than those in the patients with no response or progressive disease (NR or PD) (41.3 +/- 0.5 degrees C and 39.8 +/- 0.4 degrees C), but the difference was not significant. Of the 73 cases with HCC who were evaluated by computed tomography (CT), CR was achieved in 7 (10%), PR in 15 (21%), NR in 37 (51%), and PD in 14 (19%). Of the 45 cases involving liver metastases evaluated by CT, CR was achieved in 3 (7%), PR in 17 (38%), NR in 12 (27%), and PD in 13 (29%). The 1-year cumulative survival rate for HCC patients was 30.0%, and the 5-year survival rate was 17.5%. The 1-year survival of non-HCC patients was 32.5%, and the longest survival was 30 months. The sequelae of hyperthermia included focal fat necrosis in 20 patients (12%), gastric ulceration in 4 (2%), and liver necrosis in 1 (1%). The sequelae of thermometry were severe peritoneal pain in seven patients (11%), intraperitoneal hematoma in one (1%), and pneumothorax in one (1%). CONCLUSION: Even though the thermometry results for liver tumors were not satisfactory, the treatment results are promising. Further clinical trials of RF capacitive hyperthermia for the treatment of advanced liver tumors should be encouraged.

Bile Duct Neoplasms↗

Reduction of hypoxic cells in solid tumours induced by mild hyperthermia: special reference to differences in changes in the hypoxic fraction between total and quiescent cell populations.

C3H/He mice bearing SCC VII tumours received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps in order to label all proliferating (P) cells. The tumours were then heated at 40 degrees C for 60 min. At various time points after heating, tumour-bearing mice were irradiated while alive or after being killed. Immediately after irradiation, the tumours were excised, minced and trypsinized. The tumour cell suspensions obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labelling, which could be regarded as quiescent (Q) cells, was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P+Q) tumour cell population was determined from the irradiated tumours that were not pretreated with BrdU. The MN frequency of BrdU unlabelled cells was then used to calculate the surviving fraction of the unlabelled cells from the regression line for the relationship between the MN frequency and the surviving fraction of total (P+Q) tumour cells. In general, Q cells contained a greater hypoxic fraction (HF) than the total tumour cell population. Mild heating decreased the HF of Q cells more markedly than in the total cell population, and the minimum values of HFs of both total and Q cell populations were obtained 6 h after heating. Two days after heating, the HF of total tumour cells returned to almost that of unheated tumours. In contrast, the HF of Q cells did not return to the HF level of unheated tumours until 1 week after heating. It was thought that irradiation within 12 h after mild heating might be a potentially promising therapeutic modality for controlling radioresistant Q tumour cells.

Animals↗

Cell-killing efficiency and number of platinum atoms binding to DNA, RNA and protein molecules of HeLa cells treated with combinations of trans-diaminedichloroplatinum(II) and hyperthermia.

The effect of hyperthermia on the cell-killing efficiency of Pt atoms binding to DNA, RNA and protein molecules was examined. HeLa S-3 cells were treated with 195mPt-radiolabeled trans-diaminedichloro-platinum(II) (TDDP) for 60 min at various temperatures, and the relationship between the lethal effect and the number of Pt atoms binding to DNA, RNA and proteins was examined. The mean lethal concentration (D0) of TDDP for a 60-min treatment at 0, 25, 37, 40, 42 and 44 degrees C was 1714, 1016, 302, 179, 125 and 42.5 microM, respectively. (D0 is defined as the dose that would give an average of one lethal event per member of the population; for further details, see Fig. 1). By using identically treated cells, the numbers of Pt-atoms combined with DNA, RNA and protein molecules were determined in the subcellular fractions. Thus, the D0's given as the drag concentrations were replaced with the number of Pt-atoms combined in each fraction. Then, the cell-killing efficiency of the Pt atom was expressed as the reciprocal of the number of Pt-atoms combined and was calculated for each molecule. The efficiency for DNA was 0.206, 0.273, 0.779, 1.28, 1.77 and 5.14 x 10(3) nucleotides, respectively, for the conditions described above. It seemed that hyperthermia potentially interacted not only with bifunctional, but also with monofunctional bonds. Thus, it was concluded that TDDP was markedly less cytotoxic than cis-diaminedichloroplatinum (CDDP) at 37 degrees C, but was more cytotoxic than CDDP at 44 degrees C.

Cell Death↗

Augmentation in chemosensitivity of intratumor quiescent cells by combined treatment with nicotinamide and mild hyperthermia.

C3H/He and Balb/c mice bearing SCC VII and EMT6/KU tumors, respectively, received continuous administration of 5-bromo-2'-deoxyuridine (BrdU) for 5 days using implanted mini-osmotic pumps to label all proliferating (P) cells. Nicotinamide was administered intraperitoneally before cisplatin injection and/or tumors were locally heated at 40 degrees C for 60 min immediately after cisplatin injection. The tumors were then excised, minced and trypsinized. The tumor cell suspensions were incubated with cytochalasin-B (a cytokinesis-blocker), and the micronucleus (MN) frequency in cells without BrdU labeling (quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in total (P+Q) tumor cells was determined from tumors that had not been pretreated with BrdU labeling. The sensitivity to cisplatin was evaluated in terms of the frequency of induced micronuclei in binuclear tumor cells (MN frequency). In both tumor systems, the MN frequency in Q cells was lower than that in the total cell population. Nicotinamide treatment elevated the MN frequency in total SCC VII cells. Mild heating raised the MN frequency more markedly in Q cells than in total cells. The combination of nicotinamide and mild heat treatment increased the MN frequency more markedly than either treatment alone. In total SCC VII cells, nicotinamide increased 195mPt-cisplatin uptake. Mild heating elevated 195mPt-cisplatin uptake in total EMT6/KU cells. Cisplatin-sensitivity of Q cells was lower than that of total cells in both tumor systems. Nicotinamide sensitized tumor cells including a large acutely hypoxic fraction, such as those of SCC VII tumors, through inhibition of the fluctuations in tumor blood flow. Tumor cells including a large chronically hypoxic fraction such as Q cells were thought to be sensitized by mild heating through an increase in tumor blood flow.

Animals↗

Effects of bioreductive agents, tirapazamine and mitomycin C, on quiescent cell populations in solid tumors, evaluated by micronucleus assay.

Mice bearing transplantable solid tumors received 10 intraperitoneal administrations of 5-bromo-2'-deoxyuridine (BrdU) to label the proliferating (P) tumor cells, and were then irradiated with 60Co gamma-rays or injected with cis-diamminedichloroplatinum (II) (cisplatin). The tumor cells were isolated and incubated with cytochalasin-B (a cytokinesis blocker). The micronucleus (MN) frequency in the cells without BrdU labeling, which were regarded as quiescent (Q) cells in the tumor, was determined using immunofluorescence staining for BrdU. The MN frequency in the total (P + Q) tumor cell population was determined from tumors that were not pretreated with BrdU. Pretreatment with tirapazamine, a bioreductive agent, could enhance the sensitivity of tumor cells, including Q cells, to radiation more markedly than mitomycin C pretreatment as judged from an in vivo assay immediately after irradiation. Post-irradiation administration of tirapazamine produced a large post-irradiation radiosensitizing effect on both the total and Q tumor cell populations in vivo. Cisplatin treatment combined with tirapazamine demonstrated that tirapazamine also has a chemosensitizing potential for both the total and Q tumor cell populations. We confirmed that the sensitivity of Q cell populations to radiation and chemotherapy using cisplatin can be enhanced by combined treatment with tirapazamine.

Animals↗

Modification of the response of a quiescent cell population within a murine solid tumour to boron neutron capture irradiation: studies with nicotinamide and hyperthermia.

C3H/He mice bearing SCC VII tumours received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps, to label all proliferating (P) cells. 20 min after intraperitoneal injection of sodium borocaptate-10B (BSH), or 3 h after oral administration of dl-p-boronophenylalanine-10B (BPA), the tumours were irradiated with thermal neutrons. To modify the uptake dose of 10B, nicotinamide (NA) was intraperitoneally injected 60 min before the administration of 10B-compounds and/or the tumours were heated to 41.5 degrees C for 20 min immediately before irradiation. After irradiation, the tumours were excised, minced and trypsinized. The tumour cell suspensions were then incubated with cytochalasin-B (a cytokinesis-blocker). The micronucleus (MN) frequency in cells not BrdU-labelled (quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. With or without the administration of 10B-compounds, the sensitivity of Q cells was lower than that of total (P + Q) tumour cells. With thermal neutron irradiation in the presence of either BPA or BSH, the MN frequency in each cell population was increased. A greater increase in the MN frequency of total tumour cells was observed after thermal neutron irradiation in the presence of BPA than in the presence of BSH. The distribution of 10B from BPA into tumour cells was thought to be more dependent on the uptake ability of the tumour cells than that from BSH. Sufficient quantity of 10B from these two 10B-compounds to cause a highly lethal event inside the cancer cell with thermal neutron irradiation could not be delivered to Q cells. When NA and/or heat treatment were combined with 10B-compound administration, NA increased MN frequency in the BSH treated total cells, and heat treatment elevated MN frequency in Q cells. From the viewpoint of cell kill effect, the combined treatment with nicotinamide and heat treatment was more useful than treatment with either nicotinamide or heat treatment alone, not only in the total tumour cells but also in the Q cells.

Animals↗

An attempt to enhance chemosensitivity of quiescent cell populations in solid tumors by combined treatment with nicotinamide and carbogen.

cis-Diamminedichloroplatinum(II) (cisplatin) was intraperitoneally injected into mice bearing SCC VII or EMT6/KU tumors after ten administrations of 5-bromo-2'-deoxyuridine (BrdU) to label all the proliferating tumor cells. The tumors were excised 1 h after the cisplatin injection, minced, and trypsinized. The tumor cell suspensions were then incubated with cytochalasin-B (a cytokinesis blocker). The micronucleus frequency was determined, using immunofluorescence staining for BrdU. Cells that were not labeled with BrdU were regarded as quiescent. The micronucleus frequency in the total number of tumor cells was determined in tumors that had not been pretreated with BrdU. To modify the sensitivity to cisplatin, nicotinamide was intraperitoneally injected before the administration of cisplatin or mice were placed in a circulating carbogen (95% O2, 5% CO2) chamber for 30 min after cisplatin administration. In both tumor systems, the micronucleus frequency in quiescent cells was lower than that in the total cells. Nicotinamide pretreatment increased the micronucleus frequency in total and in quiescent cells in both tumor systems, and to a higher extent in total cells. The combination of nicotinamide and carbogen increased the micronucleus frequency more markedly than treatment with either nicotinamide or carbogen alone. In total cells of both tumors, the nicotinamide injection increased the uptake of [195mPt]cisplatin. The combined treatment raised the uptake more markedly than did treatment with either agent alone. In total cells of the SCC VII tumor, these increases in micronucleus frequency and the [195mPt]cisplatin uptake following nicotinamide or combined pretreatment were significant. In both tumors, carbogen breathing also elevated the micronucleus frequency to some degree in total and quiescent cells and the [195mPt]cisplatin uptake in total cells. The combined nicotinamide and carbogen treatment was considered to be useful for sensitizing tumor cells to chemotherapy with cisplatin in vivo.

Animals↗

Radiation therapy for T1,2 glottic carcinoma: impact of overall treatment time on local control.

PURPOSE: Local control probabilities of T1,2 glottic laryngeal cancer were evaluated in relation to dose and fractionation of radiation therapy (RT). MATERIALS AND METHODS: Between 1975 and 1993, 96 T1N0M0 glottic cancers and 32 T2N0M0 glottic cancers were treated with definitive RT. Total RT dose was 60-66 Gy/2 Gy for most of the T1 and T2 tumors, although 10 T2 tumors were treated with hyperfractionation (72-74.4 Gy/1.2 Gy bid). Of the 128 patients, 90 T1 glottic tumors and 30 T2 glottic tumors were followed for > 2 years after treatment. Multivariate analyses using the Cox proportional hazards model and a logistic regression analysis were performed to evaluate the significance of prognostic variables on local control. RESULTS: The 5-year local control probability for T1 tumors was 85%, whereas that for T2 tumors was 71%. Multivariate analyses demonstrated that only overall treatment time (OTT) was a significant variable for local control. Total RT dose, normalized total doses at a fraction size of 2 Gy, and fraction size were not significant. Local control probability of T1 tumors with an OTT of 42-49 days was significantly higher than that of tumors with an OTT of > 49 days (P < 0.02). Only a 1-week interruption of RT, due to holidays, significantly reduced the 5-year local control probability of T1 glottic tumors from 89 to 74% (P < 0.05). CONCLUSIONS: These results indicate that OTT is a significant prognostic factor for local control of T1 glottic tumors.

Adult↗

Clinical usefulness of determining the rate of thermal clearance within heated tumors.

Between June 1987 and June 1988, 28 patients (28 tumors) with liver, retroperitoneal, intrapelvic, or superficial tumors were treated with hyperthermia combined with radiotherapy and/or chemotherapy. Hyperthermia was administered once or twice a week for 30-60 min per session, up to a total of 2-11 sessions, with an 8-MHz RF capacitive heating device. Blood flow in the tumors was evaluated from the rate of thermal clearance (TCR) using the bio-heat transfer equation. The TCR was measured in the middle of the first heating session and at the end of the last heating session by turning off the output power of the heating device. For 9 patients, contrast-enhanced CT scans were taken and CT numbers at the centers of tumors were measured before and after the entire course of hyperthermia. Changes in TCR were closely related to average tumor center temperature, changes in CT number, and tumor response. When smaller and more superficial tumors were treated by hyperthermia combined with radiotherapy and/or chemotherapy that consisted of many heating sessions and during which a high average tumor center temperature was achieved, a better tumor response was obtained. The better the tumor response, the higher the local control rate became. The cause-specific survival rate of patients who achieved good tumor responses was higher than that of patients who showed poor tumor responses. Changes in TCR and CT number in heated tumors were useful and important indicators of tumor response to hyperthermia.

Adolescent↗

Relationship between cell-killing efficiency and number of platinum atoms binding to DNA, RNA, and protein molecules in HeLa cells treated with cis-diamine(glycolato)platinum(II).

HeLa S-3 cells were treated with 195m Pt-radiolabeled cis-diamine(glycolato)platinum(II) (254-S) under various conditions, and the relationship between the lethal effect and the numbers of Pt atoms binding to DNA, RNA, and proteins was examined. The mean lethal concentrations for the cells treated with 254-S at 37 degrees C for 0.5, 1, 2, and 3 h were 67.1, 47.0, 26.8 and 8.1 microM, respectively. Using identically treated cells, we determined the numbers of Pt atoms combined with DNA, RNA, and protein molecules after fractionation of the cells. In this way, the D 0 values (D 0, the dose that causes an average of one lethal event per member of the population), expressed as the drug concentration, could be related to the number of Pt atoms combined with each fraction. The efficiency of the Pt atom in killing the cells, expressed as the reciprocal of the D 0 values, was then calculated for each fraction. The results suggested that DNA was the primary target for cell killing by 254-S. The target volumes for DNA were 3.96, 4.97, and 11.77 x 10(4) nucleotides for 1-, 2-, and 3-h treated cells, respectively. In terms of the target volume, the cell-killing effects of 254-S were comparable to those of cis-diamine-dichloroplatinum(II) (CDDP), for which the target volumes under identical conditions were determined to be 5.17, 5.71, and 10.3x10 4 nucleotides, respectively, while in terms of the mean lethal dose (D 0), the cell-killing effects of 254-S were lower than those of CDDP by a factor of 5.1 (47.0/9.3), 4.0 (26.8/6.7), or 2.5 (8.1/3.2) for 1-, 2-, or 3-h treatment, respectively.

Antineoplastic Agents↗

[The clinical significance of glitter-cells in the urine during urinary tract infection].

To clarify the relationship between glitter-cells and urine osmotic pressure, neutrophils were isolated from venous blood of 4 normal volunteers and incubated in urine specimens with different osmotic pressures. Glitter-cells were detected in the urine with 100-400 mOsm/l. The rate of glitter-cells in neutrophils incubated for 4 hours were significantly less than those incubated for 0 minute (p < 0.05). We clinically investigated the relationship between the presence of glitter-cells in fresh urine and the site of urinary tract infection (UTI) or organisms isolated from urine. Fresh urine samples were obtained from 95 patients (55 male and 40 female). Urine samples were examined for bacteriuria by the quantitative culture method, and significant bacteriuria was defined as more than 10(5)/ml of bacilli for midstream urine or as more than 10(4)/ml for urine collected by catheterization. Leukocytes and glitter-cells in the unspun and unstained urine were counted on a disposable slide using a counting chamber. Patients with upper UTI showed a significantly higher incidence of glitter-cells than patients with lower UTI (p < 0.05). Patients with glitter-cells had a significantly higher incidence of polymicrobial infections than those without glitter-cell (p < 0.05). These findings suggest that patients with glitter-cells in the urine show upper UTI (pyelonephritis) and polymicrobial infections.

Adolescent↗