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Biomedical subjects

Y Shibamoto

Publications and source records attributed to Y Shibamoto.

At least 109 records · Page 6Linked to original sources
PubMed1994

Assessment of the proliferative activity and radiosensitivity of human tumours using the cytokinesis-block micronucleus assay.

We established an in vitro cytokinesis-block micronucleus assay of human tumours for estimation of the proportion of cells undergoing mitosis (the dividing fraction, DF), the time for the number of nuclei to double and the radiosensitivity in terms of the micronucleus frequency, based on a concept described previously. Under certain conditions, the nuclear number doubling time (NNDT) was considered to represent the potential doubling time. Tumour specimens obtained at surgery were disaggregated into single-cell suspensions and were directly cultured in the presence of cytochalasin B with or without irradiation. At various intervals, the percentage of multinucleate cells (the plateau value represented the DF), the average number of nuclei per cell and the number of micronuclei in binucleate cells were determined. DF and NNDT values were obtained in 58 of the 73 tumours investigated, and the micronucleus frequency was obtained in 54 of these 58 tumours. The DF ranged from 4.1% to 71% and the NNDT ranged from 3.1 to 83 days. A DF > or = 20% was associated with a higher recurrence rate in patients undergoing curative operation. A correlation was found between the NNDT and the time to relapse in patients with recurrent disease. The average number of micronuclei per binucleate cell at 2 Gy of irradiation (after subtraction of the value at 0 Gy) ranged from 0.052 to 0.35. Tumours which produced more micronuclei after irradiation showed a better response to radiotherapy. This assay can be readily performed on human tumours and appears to have promise as a predictive assay for radiation therapy.

Adenocarcinoma↗
PubMed1994

Reduction of the radiation dose for intracranial germinoma: a prospective study.

Intracranial germinoma has usually been treated with radiation doses of 50 Gy or more, but it is unclear whether such doses are actually necessary to cure this radiosensitive tumour. At our institution, the standard radiation dose for intracranial germinoma was 60 Gy in the 1960s, but the dose has prospectively been reduced stepwise to 40-45 Gy. In this paper, the treatment outcome was assessed in 84 patients (47 with histologically confirmed disease and 37 diagnosed clinically in the post-computerised tomography era) enrolled in both prospective and retrospective series. The 5 and 10 years survival rates for all 84 patients were 88% and 83% respectively, and the corresponding relapse-free survival rates were 88% and 85%. The 10-year relapse-free survival rate was 88% for 31 patients receiving 19-47 Gy (median 42 Gy) to the primary tumour, 92% for 28 patients receiving 48-52 Gy (median 50 Gy), and 83% for 25 patients receiving 54-62 Gy (median 60 Gy), and there was no significant difference among the three groups. In-field local recurrence only developed in one patient who received 40 Gy over a protracted period and one patient who received 60 Gy. A tumour size < 3 cm and treatment in the post-computerised tomography era were associated with a better prognosis according to univariate analysis, while age, sex, tumour site, treatment volume, the radiation dose to both the primary and the spinal cord and the extent of surgical resection did not influence the prognosis. In contrast, none of these factors had a significant influence in multivariate analysis. In conclusion, intracranial germinomas < or = 4 cm in size can usually be cured with 40-45 Gy of radiation, thus avoiding the major adverse effects of brain irradiation.

Adolescent↗
PubMed1994

Intraoperative radiation therapy for brain tumors with emphasis on retreatment for recurrence following full-dose external beam irradiation.

We performed intraoperative radiotherapy (IORT) in 19 patients with various brain tumors. IORT was given for primary tumors in 2 patients with malignant glioma, but was used for treating recurrent tumors in the other 17 patients. The former 2 patients respectively received 33 Gy by IORT alone and 30 Gy by IORT in combination with 50 Gy of external beam radiotherapy (EBRT), and survived for 12 and 9 months. The latter 17 patients had received EBRT at 4 to 112 months before IORT. In this group, single doses of 23-40 Gy were delivered by IORT after removing as much tumor as possible. The median survival time after IORT was 12 months for 9 patients with glioblastoma or anaplastic astrocytoma, while it was 51 months for 8 patients with less infiltrative tumors (ependymoma, anaplastic ependymoma, and anaplastic oligodendroglioma). One patient with ependymoma and another with anaplastic ependymoma are currently alive with no evidence of disease at 7 and 11 years after IORT, respectively. Symptomatic brain necrosis occurred in 3 patients following IORT, but the symptoms were relieved in 2 of them by the removal of necrotic brain tissue. It is concluded that IORT combined with extensive tumor removal has an acceptable toxicity in previously irradiated patients and can be effective for selected recurrent malignant brain tumors.

Adult↗
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

Supratentorial low-grade astrocytoma. Correlation of computed tomography findings with effect of radiation therapy and prognostic variables.

BACKGROUND: In supratentorial low-grade astrocytoma, radiation therapy effects and prognostic factors, especially with respect to computed tomography (CT) findings, are not yet well established. A retrospective analysis of 119 patients with this disease (histologically confirmed ordinary astrocytoma) therefore was conducted. METHODS: Between 1965 and 1989, 101 patients received postoperative radiation therapy, whereas 18 patients received surgery alone. Radiation was directed to the tumor plus a 1- to 3-cm margin in almost all cases; the dose range was 41 to 66 Gy (mean, 57 Gy). CT scan was performed before treatment on 74 patients. Postoperative survival rates were compared by both univariate and multivariate analyses. RESULTS: The 5- and 10-year survival rates for the irradiated group were 60% and 41%, respectively, which were significantly better than those for the surgery-alone group (37% and 11%, P = 0.048). Among various potential prognostic factors for the irradiated patients, only a lower age was associated with a better prognosis. Sex, tumor site (deep-seated or not), extent of surgery, radiation dose and field, and adjuvant chemotherapy did not influence the prognosis significantly. Among various CT findings, a clear tumor margin, a maximum tumor area less than 25 cm2, presence of a cyst, and lack of mass effect were associated with a better prognosis on univariate analysis (P = 0.02-0.12), but contrast enhancement was not related to prognosis. On multivariate analysis, however, mass effect was the only significant factor. CONCLUSIONS: Radiation therapy appears definitely to be effective in improving the prognosis for low-grade astrocytoma. Younger age, and the absence of mass effect determined by CT, were associated significantly with a better prognosis.

Adolescent↗
PubMed1993

Osteocyte viability after high-dose irradiation in the rabbit.

The effects of high-dose irradiation on the metabolism of osteocytes were examined with respect to RNA synthesis. A single 50-Gy dose of high-energy electron beam was given to the proximal tibia of rabbits. RNA synthesis by osteocytes was quantified by counting the silver grains on autoradiographs of cultured bone fragments, using 3H-cytidine as a tracer. At four, 12, and 52 weeks after irradiation, RNA synthesis by the irradiated osteocytes was 72, 62, and 79%, respectively, of that by nonirradiated osteocytes. The proportion of labeled osteocytes, conversely, was not reduced at four and 12 weeks, but was significantly reduced at 52 weeks after irradiation. The reduction in the RNA synthesis of osteocytes occurs fairly quickly, whereas reduction in the number of viable osteocytes occurs slowly as a delayed sequela. Histologic examination showed that the partial recovery of RNA synthesis observed at 52 weeks was attributable to the appearance of a fraction of new osteocytes, i.e., subendosteal apposition of new bone to the original, degrading cortex. These observations demonstrate the process of recovery from radiation damage.

Animals↗
PubMed1993

[Etiology of cholelithiasis].

The incidence of gallstone has been gradually increased in the last few decades in Japan and the recent study revealed that approximately 15% of the autopsy cases had biliary stones. In the last 25 year interval, the nature of gallstones was greatly changed. In detail, the incidences of cholesterol gallstone and black stone were increased from 46.7% to 66.9% and from 0.8% to 12.1%, respectively, whereas that of calcium bilirubinate stone was decreased from 41.5% to 21.0% of the whole cholelithiasis cases. The factors influencing these changes were probably due to recent increase of fat diet intake and decrease of ascariasis by improvement of environmental hygiene. However, the factors that caused the change in black stone has not been defined.

Adolescent↗
PubMed1992

Pharmacokinetics of intratumoral RK-28, a new hypoxic radiosensitizer.

RK-28 is one of the new hypoxic cell radiosensitizers being developed in Japan and has been tested clinically. To reduce its toxicity and increase its sensitizing activity, intratumoral injection of RK-28 was performed during intraoperative radiation therapy for pancreatic cancer. This report presents the results of pharmacokinetic studies performed in 10 of the 17 patients who were administrated intravenous or intratumoral RK-28 during intraoperative radiation therapy. No adverse effects were noted following intravenous or intratumoral injection of the drug. Pharmacokinetic studies demonstrated several metabolites of RK-28 in both serum and tumor tissues. After intratumoral injection, the tumor drug concentration ranged from 123 micrograms/g to 9,292 micrograms/g just after intraoperative radiation therapy (30-50 min after injection of the compound), while the serum concentration ranged from 4.1 to 9.8 micrograms/ml. The tumor drug concentration was 23.3 micrograms/g at 45 min after intravenous injection of RK-28. Thus, intratumoral injection of RK-28 was superior to intravenous administration in this pharmacokinetic study. The combination of intraoperative radiation therapy and intratumoral injection of RK-28 appears to be a feasible treatment method.

Adult↗
PubMed1992

Metabolic rate modification of nitrotriazole radiosensitizers by sulfur substitution of side chain.

The pharmacokinetic properties and radiosensitizing activities in vitro and in vivo of a series of 3-nitro-1,2,4-triazole (NTA) derivatives with a -CH2(C = Y)NH(CH2)nZCH3 (Y, Z = O or S; n = 2 or 3) group in the side chain at N-1 position of NTA were investigated with respect, particularly, to the effects of sulfur substitution in the side chain of NTA. The sulfur substitution for an oxygen atom in the side chain NTA radiosensitizers increased the rho value, but gave rise to little effect on the one-electron reduction potential. The derivatives bearing a thioether group (-CH2SCH3) in the side chain were slightly less effective both in vitro on hypoxic EMT6/KU cells and in vivo on SCCVII tumors than their oxygen analogs (-CH2OCH3). The thioether compounds tended to metabolize rapidly. The thioamide compound showed high sensitizing activity in vitro, but metabolized very slow.

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↗
PubMed1992

Radiation therapy for juvenile pilocytic astrocytoma of the pituitary stalk. Case report.

A case of juvenile pilocytic astrocytoma of the pituitary stalk is reported. The patient presented with diabetes insipidus and growth retardation. Magnetic resonance (MR) imaging was useful in diagnosing the lesion. Although the tumor could not be completely removed by surgery, radiotherapy was effective and the residual tumor disappeared 6 months after irradiation. The patient's condition has remained stable and no recurrence has been observed by MR imaging in the 4 years since radiation therapy.

Astrocytoma↗
PubMed1992

[Radiation therapy of pancreatic cancer].

We have been using external beam radiotherapy (EBRT) and intraoperative radiotherapy (IORT) for both resectable and unresectable pancreatic cancer patients. EBRT (50-60 Gy) was combined with IORT (25-33 Gy) whenever possible, but otherwise EBRT or IORT was given alone. In patients with unresectable tumor but no distant metastasis, the median survival time (MST) was 7.5 months (M) for the EBRT group and 9 M for the EBRT+IORT group. These MST's were significantly longer than the MST of 3 M of patients who had been treated without radiation (historical control). In non-Stage IV patients undergoing non-curative resection, the MST was 12.5 M for the EBRT group, 15.5 M for the EBRT+IORT group, and 7 M for the historical control. In patients undergoing macroscopic curative resection, the MST was 14 M for the EBRT group, 10 M for the EBRT+IORT group, and 10.5 M for the historical control. In Stage IV patients (with distant metastasis), the MST was 4.5 M for the EBRT group, 4 M for the EBRT+IORT group, 2 M for the IORT group, and 2.5 M for the historical control. Thus, radiotherapy appeared useful especially in non-Stage IV patients undergoing non-curative or no resection. A decrease or relief of pain was obtained in 90% of patients with unresectable lesions. Radiotherapy seems to play an important role in the treatment of pancreatic cancer but more aggressive combined treatment seems to be necessary to further improve the dismal prognosis of pancreatic cancer patients.

Combined Modality Therapy↗
PubMed1991

Estimation of the dividing fraction and potential doubling time of tumors using cytochalasin B.

We devised a new in vitro method to estimate the proportion of dividing cells and the potential doubling time (Tpot) of tumors using the same technique as with the cytokinesis-block micronucleus assay. The usefulness of this methodology was confirmed by comparing the data with those obtained by flow cytometry after bromodeoxyuridine (BrdUrd) incorporation. Xenografted human and murine tumors were excised 0.5-8 h after BrdUrd injection and disaggregated to single cells. A portion of these cells was then plated in dishes to which 1 or 2 micrograms/ml cytochalasin B were added. These concentrations of cytochalasin B blocked cytokinesis but not karyokinesis with the result that cells became multinucleate after mitoses. At every 12 or 24 h of culture, the proportion of multinucleate cells and the total number of nuclei and cells were scored. The remaining cells were analyzed with a flow cytometer and the BrdUrd-labeling index and Tpot were determined. In all 8 tumor lines studied, the proportion of multinucleate cells reached a plateau within 3-7 days of culture, and we therefore defined the dividing fraction as the plateau value. The dividing fraction ranged between 33 and 98% and clearly tended to be high in rapidly growing tumors. A significant correlation was seen between the dividing fraction and BrdUrd-labeling index (r = 0.74, P less than 0.001). The increase in the average number of nuclei per cell also tended to be higher in rapidly growing tumors. The Tpot was estimated as the time for this nucleus/cell ratio to reach 2.0. In 7 of 8 tumor lines, Tpot values estimated by this method compared reasonably with those estimated by the BrdUrd method. Therefore, this simple technique, originally developed for radiosensitivity prediction, would also seem to be useful in estimating tumor proliferative activity.

Animals↗
PubMed1991

A radiotherapeutic experience for localized extranodal non-Hodgkin's lymphoma: prognostic factors and re-evaluation of treatment modality.

Between 1966 and 1988, 149 patients were treated with radiotherapy for localized extranodal lymphoma. The average total dose given was 39.8 Gy for low grade disease and 48.7 Gy for all other disease. Of the 149 patients, 60 also received adjuvant chemotherapy. Twenty-four had low grade lymphoma, 109 had intermediate grade disease, and 16 had high grade disease, histologically. The distribution of histological grade and T/B phenotype varied with the primary site. Low grade lymphomas were found mainly in the orbit, and T-cell lymphomas were found in the nasal cavity and nasopharynx. The 5-year survival rates according to tumor location were 89% for oral cavity, 86% for paranasal sinus, 83% for thyroid, 69% for orbit, 47% for Waldeyer's ring (WAR), 44% for testis, 23% for CNS, 21% for nasal cavity and 60% for other sites. Histological grade and T/B phenotype both had prognostic importance. Combined chemotherapy significantly improved the survival rate only for disease with intermediate or high grade histology. Other prognostic factors according to the primary site were the bulk of lymph node for WAR disease, the radiation dose for CNS disease, bone erosion for orbital disease, stridor for disease of the thyroid, and the tumor stage for disease of both the testis and the thyroid.

Adolescent↗
PubMed1991

Variations of the hypoxic fraction in the SCC VII tumors after single dose and during fractionated radiation therapy: assessment without anesthesia or physical restraint of mice.

Variations of the hypoxic fraction (HF) after single dose (13 Gy or 4 Gy) and during fractionated (5 fractions of 4 Gy, 1 or 2 fractions per day) radiation therapy were studied in SCC VII tumors implanted subcutaneously in the hind legs of C3H/He/Jms mice using the paired survival curve method. Whole-body irradiation was delivered to tumor-bearing mice without anesthesia or physical restraint, because both are known to increase the HF artificially. The HF decreased after a single 13 Gy dose in a biphasic fashion: extremely rapidly within 1 hr and comparatively slowly during the following 12-72 hr. On the other hand, nearly no fall of HF was observed in 24 hr following a single 4 Gy dose. Also, reoxygenation was found to occur more rapidly in the interfraction period as the number of fractions of 4 Gy increased irrespective of differences of interfraction time. However, the HF just before each radiation fraction was significantly higher than the pretreatment level for both fractionated regimens. Thus, the reoxygenation patterns observed after single low and high doses of irradiation were different from each other, and reoxygenation in each interfraction period did not always proceed in a similar manner to that after single low dose irradiation. Reoxygenation was facilitated as fractionated radiation therapy proceeded, but it was not sufficient for the HF to remain at a level comparable to that before irradiation.

Anesthesia↗
PubMed1991

A fluorinated 2-nitroimidazole, KU-2285, as a new hypoxic cell radiosensitizer.

To develop new hypoxic cell radiosensitizers, we incorporated fluorine atoms into the side chain of the 2-nitroimidazole. Of the resulting compounds, KU-2285 (a 2-nitroimidazole with an N1-substituent of CH2CF2CONHCH2-CH2OH) was considered the most useful as a hypoxic cell radiosensitizer. In this study, its in vivo radiosensitizing activity and acute toxicity were compared with those of etanidazole. The reduction potentials of KU-2285 and etanidazole were -0.96 V and -1.05 V vs Ag/Ag+ in N,N-dimethylformamide, respectively, and their respective octanol/water partition coefficients were 0.25 and 0.040. The in vivo radiosensitizing activity of KU-2285 was found to be similar to that of etanidazole at the same administration dose when assayed by an in vivo-in vitro assay, a growth delay assay, and a tumor control assay using SCC VII tumor or transplanted mammary tumor in C3H/He mice. Although the radiosensitizing activity of etanidazole was reduced when it was administered orally, there was no significant difference in the radiosensitizing activity of KU-2285 whether it was administered intravenously, intraperitoneally, or orally. The acute toxicity measured as the LD50/7 in 8-week-old female C3H/HeJ mice was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy), and 4.25 g/kg (orally) for KU-2285, whereas it was 4.75 g/kg (intravenously) for etanidazole.

Animals↗