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.
D000818:Animals; D019328:Buthionine Sulfoximine; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005978:Glutathione / Q000502:physiology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008920:Misonidazole / Q000627:therapeutic use*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
D011838:Radiation-Sensitizing Agents; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008920:Misonidazole; D005978:Glutathione