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Biomedical subjects

N Oya

Publications and source records attributed to N Oya.

At least 55 records · Page 3Linked to original sources
PubMed1994

Esophageal cancer treated with radiotherapy: impact of total treatment time and fractionation.

PURPOSE: Local control rate and survival rate of esophageal cancer treated with radical radiation therapy (RT) were analyzed with special respect to total treatment time and fractionation. METHODS AND MATERIALS: Between 1979 and 1992, 88 patients with Stages I-III esophageal cancer were treated radically with RT at Kyoto University Hospital and Wakayama Red Cross Hospital. Of the 88 patients, 52 patients were treated with conventional fractionation (1.7-2.0 Gy/day, five times/week), and the remaining 36 patients were treated with accelerated hyperfractionation (AHF). In 1989, we started AHF regimen for esophageal cancer. Daily fractionations were 2.0 Gy and 1.2 Gy (field-in-field), or 1.5 Gy and 1.5 Gy at 5- to 6-h interval. Most of the patients treated with AHF received the total radiation dose of 64-68 Gy. Twenty-seven patients were treated with intraluminal brachytherapy (IBT) as boost therapy following external RT. Fourteen patients were treated with IBT following AHF. RESULTS: The median of treatment time of AHF was approximately 2 weeks shorter than that of conventional fractionation. Local control rate at 1 year were 47% for AHF, which was significantly higher than that for conventional fractionation (22%, p < 0.05). The improvement of local control by AHF was responsible for a trend to an improved cause-specific survival (p = 0.07). Local control rates at 1 year were plotted as a function of total treatment time. The slope of the linear regression line was -2.3 +/- 0.5% per day (p < 0.025) for patients treated with external RT alone, indicating a 2.3% per day loss in local control. Pretreatment and treatment parameters were evaluated in a multivariate analysis for the end point of local control. T stage (T1, 2 vs. T3, 4; p = 0.003) and fractionation schedule (p = 0.03) were independent of prognostic significance. Patients could tolerate the AHF well, although esophageal stenosis was noted frequently as a late toxicity. CONCLUSION: Accelerated hyperfractionation was the most important treatment-related variable in this patient population. Total treatment time may have a significant impact on the treatment outcome for esophageal cancer.

Adenocarcinoma↗
PubMed1994

Combined cytokinesis-block micronucleus and chromosomal aberration assay for the evaluation of radiosensitizers at low radiation doses.

PURPOSE: Several methods have been tried for evaluating the efficacy of hypoxic cell radiosensitizers at clinically relevant low radiation doses (1-4 Gy). The cytokinesis-block micronucleus assay is known to be useful for both the in vitro and in vivo evaluation of radiosensitizers, while the chromosomal aberration assay has been commonly used to assess the mutagenicity of various agents. In the present study, the chromosomal aberration assay and the cytokinesis-block micronucleus assay were performed simultaneously to assess the radiosensitizing effect of etanidazole and KU-2285 at low radiation doses. The correlation between the two assays was also evaluated. METHODS AND MATERIALS: In vitro study: EMT-6 cells were irradiated at a dose of 1-3 Gy under hypoxic conditions with or without the drugs at 1 mM. In vivo-in vitro study: EMT-6 tumor-bearing BALB/c mice received 2-4 Gy of radiation with or without administration of the drugs at 200 mg/kg. Single-cell suspensions were then obtained in both studies and were used for the cytokinesis-block micronucleus assay and the chromosomal aberration assay. The micronucleus frequency in binucleate cells was evaluated in the former assay, and the frequency of chromosomal aberrations in metaphase cells was evaluated in the latter assay. RESULTS: In vitro study: the sensitizer enhancement ratios of etanidazole and KU-2285 were 1.73 and 2.21, respectively, in the micronucleus assay, and 1.41 and 1.79 in the chromosomal aberration assay. In vivo-in vitro study: the sensitizer enhancement ratios of etanidazole and KU-2285 were 1.18 and 1.31, respectively, in the micronucleus assay, and 1.16 and 1.42 in the chromosomal aberration assay. In both studies, a linear correlation was observed between the micronucleus frequency and the chromosomal aberration frequency. The background (i.e., the frequency at 0 Gy) of the latter assay was considerably lower than that of the former assay, especially in the vivo study. CONCLUSIONS: The chromosomal aberration assay has not yet been established as a method for evaluating the effect of radiosensitizers. However, a combination of the cytokinesis-block micronucleus assay and the chromosomal aberration assay seems to be useful for assessing radiosensitizers at low radiation doses for the following reasons: a) the chromosomal aberration assay is as sensitive as the micronucleus assay and possibly more specific, because chromosomal aberrations can be observed before cells pass through the first metaphase after irradiation and, thus, reflect quite acute damage, even though they reflect only a part of the total damage; b) the combined assay provides relatively more information for the time and labor required.

Aerobiosis↗
PubMed1994

Fluorinated 2-nitroimidazole derivative hypoxic cell radiosensitizers: radiosensitizing activities and pharmacokinetics.

PURPOSE: To assess the effects of incorporation of a CF2 group into the side chain of a 2-nitroimidazole derivative, we evaluated the in vitro and in vivo radiosensitizing activities of KU-2285 (a 2-nitroimidazole derivative with an N1-substituent of -CH2CF2CONH(CH2)nOH, n = 2) and its related compounds in comparison with those of comparable nonfluorinated compounds. The pharmacokinetics of these compounds in murine tumors was also tested. METHODS AND MATERIALS: KU-2285, KU-3202 (n = 3) and KU-3207 (n = 4) are fluorinated 2-nitroimidazole derivative compounds with similar structures. Etanidazole (a 2-nitroimidazole derivative with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds, KU-3205 (n = 3) and KU-3206 (n = 4) were also tested. The in vitro radiosensitizing activities of each compound for hypoxic cells was evaluated with a standard colony formation method. The in vivo radiosensitizing activities of these compounds were tested in female C3H/He mice bearing SCCVII tumors using an in vivo/in vitro clonogenic assay. The pharmacokinetic studies were performed in C3H/He mice bearing the SCCVII tumor. Samples were analyzed by reverse-phase high-performance liquid chromatography. RESULTS: The in vitro radiosensitizing activities of fluorinated 2-nitroimidazoles were higher than those of the nonfluorinated compounds. Although the in vivo radiosensitizing activity of KU-2285 was higher than that of etanidazole (p < 0.05), other fluorinated 2-nitroimidazoles showed less radiosensitizing activity than the comparable nonfluorinated compounds. The compound was eliminated from serum more rapidly with the increase in the number of CH2 group in the side chain of the compound in each series. CONCLUSION: Although the in vitro sensitizing activity of the fluorinated compounds was higher than that of the comparable nonfluorinated compounds, the in vivo radiosensitizing activity of all fluorinated compounds but KU-2285 was lower than that of comparable etanidazole group compounds, probably due to their lower molecular concentrations in tumor and rapid elimination.

Animals↗
PubMed1994

Reoxygenation in the SCCVII tumor after KU-2285 sensitization plus single or fractionated irradiation.

PURPOSE: Because reoxygenation of solid tumors after irradiation with a hypoxic cell sensitizer has never previously been investigated, we assessed the reoxygenation in SCCVII tumors after treatment with KU-2285 plus single or fractionated irradiation. METHODS AND MATERIALS: KU-2285 (100 mg/kg) was injected intraperitoneally into C3H mice bearing 1-cm SCCVII tumors at 30 min before a single dose of 12 Gy or three fractions of 5 Gy at 12 h intervals. Changes of the hypoxic fraction (HF) were then evaluated by the paired survival curve method. RESULTS: Since the radiosensitizing effect of KU-2285 was relatively persistent, the HF was only evaluable after 6 h of irradiation. The HF of untreated SCCVII tumors was 9.1%. After treatment with KU-2285 and 12 Gy, the HF was 25% at 6 h, 32% at 12 h, 24% at 24 h, and 7.6% at 72 h. The HF was lower at 6 h than that after radiation alone, but was similar at later periods. After three fractions of 5 Gy with or without KU-2285, the HF was 33% at 6 h in both groups, while it was 12% and 13% at 24 h for tumors pretreated with KU-2285 and those receiving radiation alone, respectively. However, a sensitizing effect of KU-2285 was indicated by the downward shift of the survival curves for tumors irradiated after exposure to this agent. CONCLUSION: Reoxygenation occurred quite efficiently in tumors receiving KU-2285 and 12 Gy. After fractionated irradiation, however, reoxygenation was similar in the KU-2285-pretreatment and irradiation alone groups.

Animals↗
PubMed1994

Comparison of radiosensitizing effect of KU-2285 and SR-2508 at low drug concentrations and doses.

PURPOSE: Since the radiosensitizing effect of KU-2285 at relatively low dose levels is not known, we investigated its efficacy at such low concentrations or doses achievable in humans with oral administration of 0.3-1.0 g/m2. METHODS AND MATERIALS: KU-2285 was tested in comparison with SR-2508 at low concentrations (0.05-0.25 mM) in vitro by the cytokinesis-block micronucleus assay and by the colony formation assay, and at low drug doses (12.5-50 mg/kg) in vivo by the in vivo-in vitro assay and by the growth delay assay using SCC VII tumors in C3H/He mice. RESULTS: In the cytokinesis-block micronucleus assay, the sensitizer enhancement ratio (SER) for KU-2285 and SR-2508 was 1.43 and 1.17 at 0.05 mM, 1.75 and 1.27 at 0.10 mM, and 2.14 and 1.69 at 0.25 mM, respectively. In the colony formation assay, the SER for KU-2285 was also greater than that for SR-2508. In the in vivo-in vitro assay, the SER for KU-2285 and SR-2508 was 1.11 and 1.04 at 12.5 mg/kg, 1.21 and 1.04 at 25 mg/kg, and 1.26 and 1.18 at 50 mg/kg, respectively. In the growth delay assay at 50 mg/kg, no tumor regrowth was observed in four of the 18 mice treated with KU-2285 + 25 Gy, although the growth delay time for the remaining mice was similar to that for SR-2508 + 25 Gy. CONCLUSION: KU-2285 was more effective than SR-2508 both at low drug concentrations in vitro and at low drug doses in vivo. These promising findings suggest the potential superiority of KU-2285 over SR-2508 as a radiosensitizer for clinical use.

Animals↗
PubMed1994

KIN-804 vs. KU-2285 as a radiosensitizer for clinical use.

PURPOSE: The in vitro and in vivo effects of two promising hypoxic cell radiosensitizers, KIN-804 (KIN) and KU-2285 (KU), were compared using four types of assays, and the acute toxicity and pharmacokinetics of KIN were investigated to evaluate the clinical applicability of the compounds. METHODS AND MATERIALS: To evaluate the in vitro effect at low radiation doses (1-4.5 Gy), the cytokinesis-block micronucleus (MN) assay using SCCVII or EMT-6 cells and the chromosomal aberration (CA) assay using EMT-6 cells were performed. In addition, an in vivo-in vitro colony assay, a growth delay assay, and a pharmacokinetic study were performed using C3H mice bearing SCCVII tumors, and the LD50/7 was determined in ICR mice. RESULTS: In the in vitro MN assay, the sensitizer enhancement ratio (SER) at 0.1, 0.25, 1, and 5 mM with SCCVII cells, and at 1 mM with EMT-6 cells was respectively, 1.45, 1.61, 2.57, 4.22, and 1.96 for KIN, and 1.57, 1.62, 2.59, 5.66, and 2.21 for KU. In the in vitro CA assay, the SER at 1 mM was 1.78 for KIN and 1.79 for KU. In the in vivo-in vitro colony assay, the SER of KIN at 50, 100, and 200 mg/kg was 1.24, 1.30, and 1.45, respectively, while the SER of KU at 100 mg/kg was 1.41. In the growth delay assay, the growth delay time for 100 and 200 mg/kg of the drug plus 20 Gy of radiation was respectively, 16.5 and 19.1 days for KIN, and 18.9 and 24.0 days for KU. In all experiments, the sensitizing effect of KIN was almost equal to that of KU. The LD50/7 of KIN was 3.6 g/kg by intraperitoneal injection, while that of KU was 3.6 g/kg by intraperitoneal injection, and the pharmacokinetic study of KIN revealed a low uptake of the drug by the brain. CONCLUSION: Both KIN and KU had a definite sensitizing effect even at lower drug concentrations or doses, suggesting their potential usefulness in clinical radiotherapy.

Animals↗
PubMed1993

In vivo radiosensitization efficacy of KU-2285 and etanidazole at clinically relevant low radiation doses.

PURPOSE: The in vivo radiosensitization efficacy of KU-2285 at clinically relevant low radiation doses (2-4 Gy) was compared with that of etanidazole using four types of assays with EMT6, SCCVII, and C3H mammary tumors. METHODS AND MATERIALS: The in vivo-in vitro cytokinesis-block micronucleus assay and the chromosomal aberration assay were used to assess the sensitizing effect at single doses of 2-4 Gy. After in vivo treatment for tumors, tumor cells were cultured in the presence of cytochalasin B for the former assay or demecolcine for the latter assay, and the micronucleus frequency in binucleate cells and the chromosomal frequency in metaphase cells were evaluated after 42 hr and 3 hr of culture. In addition, an in vivo-in vitro colony assay and a growth delay assay were performed using fractionated irradiation regimens (4 Gy x 5). RESULTS: The sensitizer enhancement ratio for 100-400 mg/kg of KU-2285 was between 1.12 and 1.42. KU-2285 was a more efficient sensitizer than etanidazole in 3 of 9 experiments and as efficient as etanidazole in the remaining six experiments. CONCLUSION: Both the micronucleus assay and the chromosomal aberration assay appeared to be very useful in evaluating the in vivo sensitizing effect at low radiation doses. KU-2285 had a definite radiosensitizing effect even at low radiation doses, and clinical trials of KU-2285 may be warranted.

Animals↗
PubMed1993

Evaluation of experimental liver tumors using fluorine-18-2-fluoro-2-deoxy-D-glucose PET.

Japanese white rabbits transplanted with VX2 liver tumors are considered to be a suitable experimental model for the evaluation of therapeutic modalities. However, there has been no adequate method of assessing the changes of tumor metabolism during treatment. In the present study, 15 rabbits with VX2 liver tumors were examined by PET using 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG). After an intravenous injection of 18F-FDG, serial arterial blood sampling was performed. One hour after tracer injection, small pieces of normal liver tissue and tumor tissue were excised to determine radioactivity. Dynamic PET images were obtained in 11 of the tumor-bearing rabbits, and tumor enzyme activities were determined in six rabbits. Fluorine-18-FDG uptake by the VX2 liver tumors was 3.5 +/- 0.9 times higher than that by the normal liver tissue; so good contrast between tumor and normal liver tissue was achieved on PET scans. The enzyme activity study showed that VX2 tumors had increased levels of hexokinase and pyruvate kinase activity, suggesting an increase of glycolysis. We conclude that transplanted VX2 liver tumors could be appropriately evaluated by 18F-FDG PET.

Animals↗
PubMed1992

Radiosensitization efficacy of KU-2285, RP-170 and etanidazole at low radiation doses: assessment by in vitro cytokinesis-block micronucleus assay.

Since the cytokinesis-block micronucleus assay is very sensitive at low radiation doses, we used it to investigate the in vitro sensitizing effects of two new hypoxic cell sensitizers (KU-2285, a fluorinated 2-nitroimidazole and RP-170, a 2-nitroimidazole nucleoside analogue) at 1-3 Gy in comparison with etanidazole. Exponentially growing EMT6 cells were treated with the drugs under aerobic or hypoxic conditions for 40 min prior to and during irradiation, after which the drugs were removed and cytochalasin B (2 micrograms/ml) was added to the medium. The number of micronuclei in binucleate cells was counted after 42 h of culture. Under aerobic conditions the three compounds at 5 mM had no sensitizing effect. Under hypoxic conditions the sensitizer enhancement ratio (SER) at 5 mM was 3.8 for KU-2285, 3.2 for RP-170, and 2.3 for etanidazole, while the oxygen enhancement ratio was 2.9. When the cells were pretreated under hypoxic conditions with drugs at 5 mM but then irradiated under aerobic conditions, KU-2285 and RP-170 had a sensitizing effect whereas etanidazole did not. The sensitizers were also tested at 0.5 and 1 mM, and the SER values were compared with those obtained at high doses (15-30 Gy) using a colony assay. The SER at low doses was higher than that at high doses for 1 and 5 mM KU-2285 and 5 mM RP-170, while the SERs were similar for all concentrations of etanidazole and the lower concentrations of KU-2285 and RP-170. These results might suggest the potential usefulness of KU-2285 and RP-170 in clinical radiotherapy.

Animals↗
PubMed1992

Pharmacokinetics of fluorinated 2-nitroimidazole hypoxic cell radiosensitizers in murine peripheral nervous tissue.

We have previously reported that KU-2285, a 2-nitroimidazole with a fluorinated N1-substituent (-CH2-CF2CONH(CH2)nOH, n = 2), was a promising hypoxic cell radiosensitizer. In this study the pharmacokinetics of KU-2285 and its related compounds (n = 3 and n = 4) were compared with those of etanidazole (a 2-nitroimidazole with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds (n = 3 and n = 4) to assess the effects of incorporation of a CF2 group. The lipophilicity of the fluorinated compounds was higher than that of etanidazole, as measured by the octanol/water partition coefficient. As the number of CH2 groups increased, the lipophilicity of the compounds in both the KU-2285 and etanidazole series increased. The brain tissue levels of the fluorinated compounds were as low as those of the etanidazole derivatives, while the biological half-lives of the fluorinated compounds in peripheral nervous tissues were shorter than those of related non-fluorinated compounds.

Animals↗
PubMed1991

A new single base substitution in a Japanese phenylketonuria (PKU) patient.

DNA analysis on phenylalanine hydroxylase (PAH) gene was performed in four Japanese PKU patients. By the Southern analysis, three patients were confirmed to be homozygous for haplotype 4, and the other one was homozygous for haplotype 2. Sequence analysis on the mutant PAH gene of this haplotype 2 patient, who was born to first-cousin parents, disclosed it to be a C-to-T transition in exon 7. This transition causes the substitution of Arg261 codon to a termination codon.

Base Sequence↗
PubMed1983

Synaptic changes in Purkinje cell dentritic spine of mouse cerebellum after neonatal administration of cytosine arabinoside.

This study was undertaken to elucidate morphological changes in the synaptic area of the Purkinje cell dendritic spines when granule cells were decreased in number. The mice were injected s.c. with 30 mg/kg b.w. of cytosine arabinoside on days 2, 3, and 4, and on days 7, 8 and 9, and were designated as group I and group II, respectively. The mice injected with saline on days 2, 3, and 4 served as control. The cerebella of the mice in each group were examined by electron microscopy on days 30, 60, and 90. Using photographs thus obtained, the synaptic length and area of Purkinje cell dendritic spines which participated in synapses with axons of granule cells were measured by computer. In the controls, these spines did not increase significantly either in synaptic length or in spine area in the duration from 30 to 90 days after birth. In the 90-day-old mice belonging to group I and group II, however, they increased by about 20% in the synaptic length and by about 35% in the spine area as compared to those in age-matched control. The elongation and enlargement show that the synaptic surface on the spine spreads to compensate for synapses lost by reduction in number of granule cells in experimental groups.

Age Factors↗
PubMed1983

Neonatal monosodium glutamate-induced lesions of hypothalamus increase intestinal fat absorption in adult mice.

The hypothalamic lesion induced by monosodium glutamate injection during the suckling period affected the absorption of fat from the intestine. Mice in group 1, in which the hypothalamic lesion included not only the arcuate nucleus, but also the basal preoptic area and two-thirds of the ventromedial nucleus, showed more efficient rates of fat absorption with high serum concentrations of immunoreactive insulin than the control. Mice in group 2, in which the hypothalamic lesion was confined mostly to the arcuate nucleus, also showed a significant increase in fat absorption, but elevated immunoreactive insulin was not found in the serum of these mice.

Aging↗
PubMed1983

Effects of excess amounts of synthetic amino acid preparations on hypothalamus of mice and kittens.

The relationship between the neurotoxicity caused by excess amounts of synthetic amino acid preparations and serum levels of a certain amino acid was examined using suckling mice and kittens. Three preparations, two of which contained aspartic acid and glutamic acid, were injected intraperitoneally into neonatal mice. Almost all the animals which were treated with the preparations containing aspartic acid and glutamic acid at a dosage of more than 40 microliters/g body weight (b.w.) showed hypothalamic lesions. The severity of these increased according to each dose increment. On the other hand, none of the animals treated with the preparation containing neither aspartic acid nor glutamic acid sustained hypothalamic lesions. All kittens injected intravenously with the preparation containing aspartic acid and glutamic acid at dosages of more than 20 microliters/g b.w. also showed hypothalamic lesions, but none of the kittens treated with dosages of less than 10 microliters/g b.w. did. Serum levels of each amino acid reached their highest values as early as 5 min after injection and then returned abruptly to the control value within 3 h.

Amino Acids↗