Enhancement of EMT6/SF tumor cell killing by mitomycin C and cyclophosphamide following in vivo administration of buthionine sulfoximine.
We have examined the effect of L-buthionine sulfoximine (BSO) treatment on the subsequent cytotoxicity of mitomycin C (Mit C) and cyclophosphamide (CYC) in EMT6/SF tumors growing in Balb/c mice. GSH content in tumors decreased to a minimum level (less than 30% of control) 12 hr after a single injection of 5 mmole/kg of BSO. The recovery of tumor GSH was protracted and did not reach control levels up to 24 hr following BSO administration. Mit C and CYC were administered 12 hr after BSO injection. Tumor cell survival reached almost the same minimum level (SF = 0.050-0.06%) 1 hour after Mit C (10 mg/kg) treatment with or without BSO. However, 24 hr after Mit C treatment, survival had increased 36-fold (SF = 1.9%) in non-BSO-treated tumors compared to only 4-fold (SF = 0.3%) in the BSO-treated tumors. A dose modifying factor (DMF) of 1.4-1.8 was observed for BSO-pretreated tumors assayed 24 hr after Mit C administration. In CYC-treated tumors, minimum surviving fractions were found 4 hr after CYC treatment with or without BSO treatment. These minimum survival levels were almost the same in BSO-treated tumors following 100 mg/kg CYC (SF = 0.03%) as in control tumors treated with 150 mg/kg CYC (SF = 0.04%). The same increase in cell survival was observed when tumor excision and assay were delayed 24 hr following CYC administration with or without prior BSO treatment. BSO treatment enhanced the cytotoxicity of CYC by DMFs of 1.6-1.9 based on the 24 hr excision assay. Depletion of tumor GSH by BSO caused enhancement of tumor cell killing by the two chemotherapy agents studied, either by increasing cytotoxicity, in the case of CYC or by decreasing PLD recovery following Mit C.
D000818:Animals; D019328:Buthionine Sulfoximine; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin; D008937:Mitomycins / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*
D008937:Mitomycins; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D016685:Mitomycin; D003520:Cyclophosphamide; D005978:Glutathione