マウス頭蓋内移植腫瘍に対するmisonidazoleの放射線増感効果と臨床応用

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The radiosensitizing effect of misonidazole was studied in an experimental system of intracranially transplanted 203-glioma in C57BL mice. When 5×10^5 tumor cells were transplanted into the right frontal area of 4-week-old male mice, all the control mice died within 3 weeks after transplantation. The experimental mice were treated with 1,000 rads of irradiation using ^<60>Co, with or without misonidazole administration, given after various lengths of time after transplantation. When used, misonidazole was given intraperitoneally in a dose of 20 mg, 30 to 60 minutes prior to irradiation. Misonidazole had no remarkable effect when the mice were treated 6 days after transplantation. However, when they were treated with misonidazole 10 days after transplantation and irradiated, the mean survival time of the mice was longer (about 6.5 weeks) than that of the mice treated by irradiation alone (about 4.5 weeks). In order to evaluate the radiosensitizing effect of misonidazole in the terminal stage to contain a large number of hypoxic tumor cells, the following in vivo assay was designed. Intracranial tumors, with or without misonidazole treatment, were removed immediately after irradiation. Then, 5×10^5 viable tumor cells were retransplanted into other groups of mice, and their survival rates were observed. While all the mice retransplanted with tumor cells treated by irradiation alone died of tumor growth within 5 weeks, those retransplanted with tumor cells treated by irradiation and misonidazole became free of tumor and survived for the observation period of 8 weeks. These results suggest the radiosensitizing effect of misonidazole. As regards the side effects, there was no notable decrease in body weight after the administration of misonidazole. On histological examination there was no specific change ascribable to misonidazole, while there were many necrotic regions after irradiation with or without misonidazole. As a clinical trial, misonidazole was given to 21 patients with brain tumors in an oral dose of 1.0g/m^2,4 to 6 hours prior to irradiation twice weekly. The total dose was limited to 10g/m^2. Because the series of patients was not large enough and because most of them were also given chemotherapy, it was difficult to distinguish the effect of misonidazole from that of conventional radiotherapy and chemotherapy. There was no remarkable side effects due to misonidazole except for nausea and vomiting in some patients. It is clear, however, that the limiting factor in the clinical dose of misonidazole is its various toxicities, such as peripheral neuropathy and gastrointestinal symptoms, which have occasionally been reported, and so the local application of misonidazole may be the next step.
日本脳神経外科学会の論文
1982-05-15

マウス頭蓋内移植腫瘍に対するmisonidazoleの放射線増感効果と臨床応用

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