Relationship between thiol depletion and chemosensitization in a transplantable murine bladder tumor.
The effect of pretreating the C3H/He mouse MBT-2 tumor with diethyl maleate (DEM), buthionine-S R-sulfoximine (BSO), or misonidazole (MISO) before administration of cyclophosphamide (CTX) was studied with the use of tumor volume-doubling time delay as an endpoint. The kinetics of glutathione (GSH) depletion and regeneration in the tumor and in the host liver were determined after treatment with the thiol-depleting agents. CTX was administered at appropriate time points. MISO was the most effective chemosensitizer at a time point at which tumor GSH content was 80-85% of the control value. Both BSO and DEM were chemosensitizers in relation to the degree they had reduced tumor GSH levels. This chemosensitization was significant at 50% GSH reduction. By combining MISO and BSO at doses lower than previously used for each agent alone, highly effective sensitization of subsequent CTX was obtained.
D000818:Animals; D019328:Buthionine Sulfoximine; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008298:Maleates / Q000627:therapeutic use; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*
D004338:Drug Combinations; D008298:Maleates; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008920:Misonidazole; D003520:Cyclophosphamide; C014476:diethyl maleate; D005978:Glutathione