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C Murayama

Publications and source records attributed to C Murayama.

At least 37 records · Page 2Linked to original sources
PubMed1991

[Effect of lisuride on experimental cerebral infarction in rats].

Lisuride is an ergot derivative with central dopaminergic (D2 agonistic) and serotonergic (5-HT1A agonistic) activity. The effect of lisuride on experimental cerebral infarction in rats was investigated. Cerebral infarction was induced by intracarotid infusion of a 50-microliters mixture in which deformed and rigid red blood cells treated with hypertonic solution were contained. Lisuride or 0.9% NaCl was administered subcutaneously 30 min before induction of cerebral infarction. Lisuride (0.01 mg/kg) not only prolonged the survival time of the animals but also suppressed cerebral edema, increase in the electrolytes content and histological damage in the brain. These results suggest that lisuride has a protective effect against cerebral infarction.

Animals↗
PubMed1990

[Radiosensitization by hypoxic cell radiosensitizer--present status of radiosensitizer].

Because of the unsuccessful clinical trials of misonidazole (MISO), many efforts have been made to find a new hypoxic cell sensitizer which is more effective and/or less toxic than MISO. In Japan, RK-28 is already under going Phase II clinical evaluation and RP-170, KU-2285 and KIH-802 have been proven to be effective both in vitro and in vivo and are also waiting further clinical trials. But in U.S.A. and England, etanidazole (SR-2508) and pimonidazole (Ro 03-8799) are under going Phase III evaluation and clinical evaluation of SR-2508 will be key opened in early next year. Now, an appropriate goal for a new radiosensitizer would be more effective and/or less toxic than SR-2508 or clinically more useful than SR-2508. Clinical trials of SR-2508 have been performed using intravenous injection, however it may be difficult to give a sensitizer intravenously on a daily basis in accordance with requirements for standard fractionated radiotherapy in a clinical setting. In contrast, RP-170 and KU-2285 have the potential to produce considerable radiosensitization under both intravenous and oral administration.

Cell Hypoxia↗
PubMed1989

Radiosensitization by a new nucleoside analogue: 1-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl-2-nitroimidazole (RP-170).

A new potent hypoxic cell sensitizer, a 2-nitroimidazole nucleoside analogue having methoxyglycerol as a sugar moiety at the N-1 position of the imidazole ring (RP-170), has been synthesized. Its radiosensitizing activities in vitro and in vivo were investigated and compared with those of misonidazole (MISO) and etanidazole (SR-2508). As might be expected from the almost identical electron affinities of the three compounds, they were equally effective against hypoxic EMT6 cells in vitro. The in vivo-in vitro excision analysis showed that RP-170 was also as effective as MISO and etanidazole to radiosensitize solid tumor cells in vivo. An intraperitoneal administration of 200 mg/kg of RP-170 and an intravenous administration of the same dose of etanidazole showed an equal sensitizer-enhancement ratio of 1.51 to solid EMT6/KU tumors. Its effectiveness was also demonstrated by growth delay assay using solid SCCVII tumors. As predicted from the low partition coefficient, RP-170 and etanidazole showed apparently lower toxicity in vivo than MISO; their LD50/14 were 4.3, 4.8, and 1.8 g/kg in our experiment, respectively. Moreover, RP-170 showed fast clearance from serum in mice (t1/2 = 10.24 min) and poor penetration into neural tissues. Although RP-170 does not show any advantages over etanidazole in terms of sensitization or toxicity, RP-170 might be preferable under certain circumstances because it can be given orally.

Animals↗
PubMed1989

KIH-802: 2-nitroimidazole-1-acetohydroxamate as a hypoxic cell radiosensitizer.

We have identified potassium 2-nitroimidazole-1-acetohydroxamate (KIH-802) as a hypoxic cell radiosensitizer potentially superior to Miso. The water-soluble acetohydroxamates of 2-nitroimidazole (KIH-802; free acid 801) and 4-nitroimidazole (KIH-852) were designed, synthesized, and evaluated by in vitro and in vivo screening against EMT6 cells. Enhancement ratios of KIH-802 and 801 were 1.92 and 1.68, respectively, compared with 1.58 for MISO all at 1 mM. These acetohydroxamates are also expected to be more effective in vitro than SR-2508 based on our previous experiments. In vivo ERs of KIH-802, 801, and 852 were 1.75, 1.50, and 1.35, respectively, compared with 1.57 for MISO all at the same dose of 200 mg/kg. The data clearly show that the addition of an acetohydroxamic acid moiety to the 2-nitroimidazole skeleton can enhance radiosensitizing ability.

Animals↗
PubMed1989

Radiosensitizing hypoxic cells with new 3-nitro-1,2,4-triazole derivatives in vitro and in vivo.

The new regioisomer derivatives 4a-f and 5a-f of 3-nitro-1,2,4-triazole (3-NTR) were synthesized for the development of new radiosensitizers of hypoxic cancer cells for radiotherapy. N(2)-Substituted 3-NTR derivatives 5a-f were stronger radiosensitizers of hypoxic cells in vitro (Chinese hamster V79 cells) than N(1)-substituted 3-NTR derivatives 4a-f, but in vivo they were weaker (SCCVII carcinoma cells inoculated into C3H/He mouse).

Animals↗
PubMed1989

[Present status of radiation sensitizers--hypoxic cell radiosensitizer].

There is a world-wide demand for a clinically usable sensitizer for radio resistant hypoxic cells. Since the unsuccessful clinical trials of misonidazole (MISO), is due to its neurotoxicity, many efforts have been made to develop new hypoxic cell sensitizers which is more effective and/or less toxic than MISO. In the U.S.A., SR-2508 (etanidazole) is currently under going phase III clinical evaluation in advanced head and neck cancers, and in England, Ro 03-8799 (pimonidazole) is also under going phase III evaluation in advanced cervical cancer. Also in Japan, many compounds were synthesized and tested with the screening systems using EMT6 and SCCVII tumors. KU-2285 is fluorinated nitroimidazole and it has a higher sensitizing effect than MISO or etanidazole. Its sensitizing effect is 1.65 at 200 mg/kg, and the LD50 value is 2.3 g/kg. Hoping for less neurotoxicity, RK-28, RP-170 and KIH-802 were synthesized. RP-170 showed the same advantages over MISO as etanidazole in terms of sensitization or toxicity and KIH-802 demonstrated an unexpectedly high sensitizing effect especially in vivo experiments. Although RK-28 has a low LD50 value, it shows rapid clearance rate from serum and is supposed to have less cumulative neurotoxicity. RK-28 has already entered to phase I clinical trial and KU-2285, RP-170 and KIH-802 are also waiting further clinical trials.

Animals↗
PubMed1988

[Development of new hypoxic cell radiosensitizer in Japan].

Basic studies in hypoxic cell radiosensitizers developed in Japan were reviewed. Because of the unsuccessful clinical trials of misonidazole (MISO), many efforts have been made to find a new hypoxic cell sensitizer which is more effective and/or less toxic than MISO. Already over a thousand drugs were tested, but the majority of them did not work in vivo or were very toxic to the animals. Finally four drugs, KU-2285, KIH-801 (802), RK-28 and RP-170, have been proven to be effective both in vitro and in vivo. All of them are derivatives of 2-nitroimidazole. The first two have different side chains of fluorinated amide and acetohydroxamic acid, respectively. The second two both have sugar moieties. Investigations are now under way to find possible clinical applicability.

Animals↗
PubMed1987

Effect of oridonin, a Rabdosia diterpenoid, on radiosensitization with misonidazole.

The radiosensitization brought about by oridonin, one of the Rabdosia diterpenoids, alone or in combination with misonidazole, was investigated in Chinese hamster V79 cells. The enhancement ratio of 1.92 was obtained when 0.01 mM oridonin and 1 mM misonidazole were administered to hypoxic cells under radiation. The enhancement ratios of oridonin and misonidazole for hypoxic cells were 1.16 and 1.59 respectively. Hence, a supra-additive effect was obtained by the combined treatment with these two drugs. Under aerobic conditions, no effect of 0.01 mM oridonin on the radiosensitization caused by misonidazole was observed.

Animals↗
PubMed1987

In vitro and in vivo radiosensitizing effects of 2-nitroimidazole derivatives with sugar component.

A new type of hypoxic cell sensitizer, 2-nitroimidazole substituted with an acyclic sugar analogue at the N-1 position of the imidazole ring (RK compounds) has been developed and tested on HeLa S3 and Chinese hamster V79 cells. As might be expected from their electron affinities, which are stronger than that of misonidazole, the abilities of RK compounds to sensitize hypoxic cells were correspondingly increased. One millimole of RK28 [1-(4'-hydroxy-2'-butenoxy)methyl-2-nitroimidazole] gave an enhancement ratio of 1.56 or 1.84 in comparison with 1.40 or 1.71 for the same concentration of misonidazole to HeLa S3 or V79 cells, respectively. RK28 showed slight cytotoxicity to aerobic HeLa S3 cells at a concentration of 5 mM after a three-hour exposure, whereas under hypoxic conditions, the agent was markedly cytotoxic. In vivo radiosensitization studies in ICR mice with Ehrlich ascites tumor indicated that RK28 produced an increase in DMF to hypoxic tumor cells with increased dose of the compound. Their DMF values were 1.63, 1.97 and 2.34 at 0.075, 0.15 and 0.3 mg/gbw of RK28, respectively. A dose of 0.3 mg/gbw of RK28 produced a DMF around 1.5 to two times greater than that resulting from the same dose of misonidazole. Pharmacokinetic studies of RK28 in ICR mice with Sarcoma-180 revealed a faster clearance from the serum and a slower decrease in the tumor than with misonidazole.

Animals↗
PubMed1984

Total body irradiation as a method of preparation for bone marrow transplantation: a new technique and review.

Recently total body irradiation has been used as a method of preparation for the bone marrow transplantation. However, it has become apparent that total body irradiation is one of the causes of interstitial pneumonia. There are several factors in total body irradiation that may induce interstitial pneumonia. 1) Total dose. Usually 10 Gy which is used in America, reduces the survival of the leukemic cells to about 0.001% while the normal tissue cells are reduced to about 1%. However there is no evidence that 10 Gy is enough for bone marrow transplantation. 2) Dose rate. A dose of 10 Gy given at a high dose rate is about 10 times more effective than at a low dose rate. However, the dose-rate effects become less pronounced when the single dose is under 2 Gy. 3) Dose fractionation. The effect on cell survival of dose fractionation is discussed. Since the recovery from the radiation damage is usually greater in normal cells than in the malignant cells, fractionated radiation will have great advantages. 4) Dose distribution and new irradiation technique. It is difficult to obtain homogeneous distribution if a single large radiation field is used. In our hospital the patients receive total body irradiation by a moving treatment couch method under X-rays exposure. Homogeneous dose distribution is achieved with this method. Total body irradiation will become an almost routine treatment method for bone marrow transplantation with multifractionated irradiation.

Bone Marrow Transplantation↗
PubMed1984

The effect of hypoxic radiosensitizer after mild hyperthermia in C3H mammary carcinoma.

The radiosensitizing effect of misonidazole after hyperthermia was investigated in C3H mammary carcinoma. The tumors transplanted into the flanks of the mice were heated in a 42.3 degrees C water bath for 30 min. When misonidazole was administrated before heating, the subsequent radiation effect was prominently enhanced, whereas post-heating administration of misonidazole did not enhance the radiation effect significantly. The effect of varying the time between heating and radiation with or without misonidazole was as follows. Without misonidazole, the radiation effect was decreased at 6 hours after heating but increased at 12 hours, then it returned to the initial level at 24 hours and remained until 96 hours after heating. With misonidazole administered 30 min before irradiation, the radiosensitizing effect was observed at 24, 48 and 96 hours after heating. However, the total effects of this procedure were almost the same as the results in the combination without heating. Changes in the hypoxic fraction after hyperthermia are also discussed.

Anaerobiosis↗
PubMed1984

Polarographic measurement of misonidazole in mouse mammary tumors.

The sensitizing effect of misonidazole, a hypoxic cell radiosensitizer, is presumed to be due to its strong electron affinity. The concentration of misonidazole in mouse mammary tumors was measured polarographically in vivo. When 1 mg of misonidazole per gram body weight was administered intraperitoneally to C3H/He mice, 0.5-0.75 mM of misonidazole was observed in the tumors 25-60 min later. The distribution of misonidazole in the tumors varied, but the mean concentrations were not significantly different except in the necrotic area and the central-superficial region, where the concentration of misonidazole tended to be lower than in the other regions. No differences in the concentration of misonidazole were observed in tumors with diameters ranging from 4 to 11 mm. The polarographic measurement of misonidazole in vivo is technically simple and can be applied to the study of hypoxic cells in tumor tissue.

Animals↗