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Biomedical subjects

Y Shibamoto

Publications and source records attributed to Y Shibamoto.

At least 163 records · Page 9Linked to original sources
PubMed1987

Evaluation of various types of new hypoxic cell sensitizers using the EMT6 single cell-spheroid-solid tumour system.

Eleven new hypoxic cell sensitizers representative of those developed in Japan between 1980 and 1985 were evaluated in vitro and in vivo in comparison with misonidazole (MISO), SR-2508, Ro 03-8799, and ANT (2-amino-5-nitrothiazole). The new compounds included 2-nitroimidazole nucleoside analogues, nitrotriazoles and other nitroaromatics, non-nitro compounds, and electron-affinic compounds that readily intercalate DNA. The sensitizing activity in the EMT6 single cells correlated not only with the reduction potential but, for some compounds, also with the reactivity with non-protein sulphydryls. The sensitizers were also tested using the EMT6 spheroids and solid tumours. The patterns of changes in sensitizer enhancement ratios (SERs) for single cells, spheroids, and solid tumours were classified into two types: (1) SERs for the three testing systems were similar; and (2) SERs decreased in the order of: single cells, spheroids, and solid tumours. Only nitroimidazole and nitrotriazole derivatives belonged to the former type. RK-28 and RK-29, 2-nitroimidazoles with sugar analogue components, had in vivo effects almost equal to those of MISO. Also 3- and 4-nitrotriazole derivatives had definite in vivo effects.

Animals↗
PubMed1987

[Present status of hypoxic cell sensitizers and PLDR inhibitors].

Clinical and basic studies in hypoxic cell radiosensitizers and potentially lethal damage (PLD) repair inhibitors were reviewed. Most clinical trails on misonidazole (MISO) show that the toxicity of MISO is a major reason for failure in the trials and an adequate selection of tumors is needed for the success. Phase III studies on SR-2508 and RO 03-8799, less toxic and more effective sensitizers, are in progress. AK-2123 and RK-28 developed in Japan are drugs with similar clinical applicability of MISO. Thiol depletion of tumors is one of the way to increase the radiosensitization. The measurement of intercapillary distance on histopathological microslide is a valuable method to select the tumors containing much hypoxic cell fractions. Stable and effective chemicals as MISO in hypoxic cell sensitization must be developed to investigate the clinical applicability of PLD repair inhibitors.

Animals↗
PubMed1987

The radiation response of SCCVII tumor cells in C3H/He mice varies with the irradiation conditions.

The radiation response of SCCVII tumor cells in C3H/He mice under various irradiation conditions was studied using an in vivo-in vitro assay. When tumor-bearing mice were irradiated without anesthesia or physical restraint, the tumor had a hypoxic fraction of 5.4%. Both anesthesia and immobilization of the tumor-bearing leg with adhesive tape produced significant increases in the hypoxic fraction (23 and 28%, respectively). Restraining the mouse in a jig without immobilizing the tumor-bearing leg also increased the hypoxic fraction (13%).

Animals↗
PubMed1986

Radiosensitization in vitro and in vivo by 3-nitrotriazoles.

A series of 3-nitro-1,2,4-triazole derivatives bearing various types of side chain (R) at the N1-position (AK-2000 series) were synthesized and their radiosensitizing effect and toxicity in vitro and in vivo were investigated, in comparison with those of Misonidazole (MISO), SR-2508, and RSU-1069. Of the fifteen 3-nitrotriazoles tested, all had sensitizing effects in vitro on hypoxic V79 cells. Also, all but one had definite effects on solid EMT6/KU and SCCVII tumors in vivo. For many of the triazole compounds, the degree of radiosensitization in vitro and in vivo appeared identical. However, they were generally less efficient, both in vitro and in vivo, than the corresponding 2-nitroimidazoles, whereas their aerobic cytotoxicity and toxicity to mice (LD50/7) were comparable to those of the 2-nitroimidazoles. Considering the sensitizing effect and toxicity, AK-2123 (R = CH2CONHC2H4OCH3) may be as useful as MISO, but none of the triazoles have been proved to be superior to SR-2508.

Animals↗
PubMed1986

Chemosensitization by buthionine sulfoximine in vivo.

The in vivo effects of buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) biosynthesis, on the cytotoxicity of cyclophosphamide (CYM), cisplatin (CDDP) and bleomycin (BLM), were examined by monitoring the changes of non-protein thiols (NPSH) in normal tissues and in the NFSa fibrosarcoma. We used the lung colony assay as a measure of tumor response and the spleen colony assay as a measure of normal tissue response to CYM. In this study, 5 mmol/kg of BSO was subcutaneously injected four times every 12 hr before administration of the above anti-neoplastic drugs. GSH levels in subcutaneous NFSa tumors decreased to 2% of the control 12 hr after the last administration of BSO, but in the bone marrow, had recovered to 41%. In the colony assays, BSO increased the anti-cancer effects of the three chemotherapeutic agents, but did not modify the bone marrow suppression by CYM. This finding was a result of the differential response of GSH depletion in the tumor and in the bone marrow. Our study demonstrates that BSO is an effective chemosensitizer of these drugs and may be of therapeutic value when used at an optimal interval.

Animals↗
PubMed1986

Radiosensitizing effect of misonidazole in combination with an inhibitor of glutathione synthesis in murine tumors.

The radiosensitizing effects of misonidazole (MISO) in combination with D,L-buthionine-S, R-sulfoximine (BSO), an inhibitor of glutathione (GSH) biosynthesis, were studied in NFSa tumors of C3H/He mice. The radiation response of tumors was assayed by the tumor growth delay time. The GSH contents in tissues were assayed by high performance liquid chromatography (HPLC). GSH content in the tumors decreased to the minimum level (45% of the control), and then gradually recovered to 75% of the control, respectively, 12 and 24 hr after the intraperitoneal injection of 5 mmole/kg BSO. On the other hand, the maximum non-protein sulfhydryl (NPSH) depletion (29% of the control) in the liver of tumor bearing mice was achieved 6 hr after the administration of the same dose of BSO, but fully recovered 24 hr later. When 5 mmole/kg BSO was injected repeatedly 4 times at an interval of 6 hr, GSH content in the tumors decreased to 19% of the control 24 hr after the first injection of BSO. The radiosensitizing effect of 0.5 mmole/kg MISO was markedly increased by this BSO treatment. The enhancement ratio (ER) of this combined treatment was 1.93. On the other hand, ERs of 1.44 and 1.16 were obtained for MISO (0.5 mmole/kg) and for 4 injections of BSO (5 mmole/kg) in combination with radiation, respectively. Although a considerable increase in the radiosensitizing efficiency of MISO in vivo by the treatment with BSO was found without any notable side effects of the combination, more studies on toxicities are needed to get a definite conclusion on the clinical applicability of the combination.

Animals↗
PubMed1986

The radiosensitizing effects of misonidazole (MISO) in combination with diethyl maleate (DEM) in mouse mammary tumors.

Large radiosensitization of C3H/He mouse mammary tumors was obtained with the combination of a non-protein sulfhydryl (NPSH) depletor, diethyl maleate (DEM), and misonidazole (MISO), compared with MISO alone over a range of MISO dose. The difference in enhancement ratios (ER's) for these two treatments was especially prominent at small MISO doses. ER's of 2.06 and 1.44 were obtained, respectively, by combined treatment with DEM (760 mg/kg) and MISO (100 mg/kg) or treatment with MISO alone. Radiosensitization of tumors by DEM alone was observed for doses over 600 mg/kg. When DEM was combined with MISO (100 mg/kg), ER's of the combination were larger than that of MISO alone, for doses over 400 mg/kg of DEM. Similarly, in case of DEM plus MISO (300 mg/kg), the ER's became larger than MISO alone, for doses over 200 mg/kg of DEM. The NPSH content in untreated tumors was 1.08 mmole/kg on the average and no changes in NPSH content was observed after MISO treatment. DEM treatment markedly reduced the NPSH content of tumors as a function of DEM dose and this decrease in NPSH was not significantly affected by MISO treatment. Tumor NPSH was reduced to 24% or less of control by administration of 760 mg/kg of DEM with or without MISO. These results are consistent with competition theory of NPSH and electron affinic radiosensitizers.

Animals↗
PubMed1986

Combined effect of buthionine sulfoximine and cyclophosphamide upon murine tumours and bone marrow.

Two and four treatments of 5 mmol kg-1 of buthionine sulfoximine (BSO) at an interval of 12 h depleted the glutathione (GSH) content in NFSa tumours of C3H/He mice, respectively, to 24.0 and 1.78 percent of the untreated controls. BSO pre-treatments every 12 h enhanced the cytotoxicity of cyclophosphamide (CYC) towards artificial lung micrometastases of NFSa tumours giving enhancement ratios (ERs) ranging from 1.75 to 1.83 and from 2.41 to 2.73, for two and four BSO pretreatments respectively. Large ERs were obtained at low CYC doses (high cell survival). Four BSO pre-treatments at an interval of 12 h did not increase the cytotoxicity of CYC to bone marrow stem cells. Our results suggest a clinical applicability of the combination of BSO and CYC.

Animals↗
PubMed1986

Variation in the hypoxic fraction among mouse tumors of different types, sizes, and sites.

Radiobiologically hypoxic fractions of 4 experimental tumors (RIF1, B16, EMT6/KU, SCCVII) of various sizes implanted subcutaneously (sc) or intradermally (id) were compared under identical conditions by using the paired survival curve assay method. The two survival curves for tumors in air-breathing and asphyxiated mice were almost parallel for EMT6/KU and SCCVII tumors, but not for RIF1 and B16 tumors. Therefore, hypoxic fractions were estimated by fitting the best parallel lines to the two sets of survival data. The values for 10 mm-diameter sc tumors in the hind legs of syngeneic mice were 4.7% for RIF1, 4.5% for B16, 14% for EMT6/KU, and 8.5% for SCCVII. The variation of the values is quite small in spite of the variety of biological characteristics of these tumors. Histological examination revealed that EMT6/KU and B16 tumors contained large necrotic areas, while SCCVII and RIF1 had small areas of necrosis. Thus, the hypoxic fraction and the proportion of necrosis in the histological specimens were not clearly correlated. The values for 6 mm and 16 mm sc EMT6/KU tumors were 5.9 and 22%, respectively, while that for 6 mm id tumors was 16%. The values for 5 mm and 18 mm sc SCCVII tumors were 0.86 and 8.4%, respectively. These results indicated that: (1) id EMT6/KU tumors had a higher hypoxic fraction than sc ones of the same size; (2) the hypoxic fraction increased with increase in tumor size in EMT6/KU tumors, while it reached a plateau at a certain size in SCVII tumors.

Animals↗
PubMed1986

An in vitro and in vivo screening system for new hypoxic cell radiosensitizers using EMT6 cells.

An experimental tumor system consisting of single cells, spheroids, and solid tumors was developed using the EMT6/KU cell-line for evaluation of new hypoxic cell sensitizers. This paper describes the radiation dose-survival curves of the system and the effects of four sensitizers [misonidazole, Ro 03-8799, KB-11 (a sulfonyltetrazole derivative), and DNIE (a dinitroimidazole derivative)] in this system. Dose-survival curves of the spheroids varied significantly depending on the irradiation conditions, but it was found that the spheroids could model the solid tumors when they were irradiated in flat-bottomed flasks. These spheroids and solid tumors contained substantial fractions of hypoxic cells, and hence were suitable for testing hypoxic cell sensitizers. Misonidazole at a concentration of 1 mM or 1 mmol/kg showed a constant enhancement ratio (ER) of 1.55 in all of the systems. The ERs of the other three compounds for single cells, spheroids, and solid tumors were 2.1, 1.9, and 1.65, respectively, for Ro 03-8799 (1 mM or 1 mmol/kg); 2.6, 1.6, and 1.0, respectively, for KB-11 (0.5mM or 0.5 mmol/kg); 1.8, 1.2, and 1.1, respectively, for DNIE (0.5mM or 0.5 mmol/kg). These results indicated that the ER for spheroids is closer to the ER for solid tumors than is the ER for single cells in most cases. It was also suggested that an efficient sensitizer in vivo shows little or no difference between its ER for single cells and that for spheroids.

Animals↗
PubMed1985

Intraoperative radiotherapy in the definitive treatment of localized carcinoma of the prostate.

A preliminary analysis of the effectiveness of intraoperative radiotherapy with an electron beam for the treatment of prostatic cancer in 14 patients is presented. The perineal approach was employed as an operative procedure for placing a treatment cone onto the tumor. The electron energy used for irradiation ranged from 10 to 14 MeV. Of five patients treated by intraoperative radiotherapy alone, four who received single doses of 3000 to 3500 cGy achieved local control. One of these patients, however, who received 3000 cGy, had a local recurrence occurred at the sixth year after the treatment. A patient treated with 2800 cGy failed. A single dose of 2000 or 2500 cGy was delivered intraoperatively to nine patients as a boost dose in conjunction with external irradiation of 5000 cGy for the treatment of pelvic lymph nodes. All nine patients achieved local control. None of the 14 patients developed any serious complication of the bladder, urethra or rectum, which has been associated with intraoperative electron irradiation. Although no definite conclusion can be drawn at present because of the small number of patients and insufficient follow-up, the results suggest that single doses of 3300 cGy by intraoperative radiotherapy alone or 2500 cGy as a boost in conjunction with external radiotherapy can be curative for prostatic cancer with minimal morbidity.

Adenocarcinoma↗