Lack of enhanced myelotoxicity with buthionine sulfoximine and sulfhydryl-dependent anticancer agents in mice.
The lethal and non-lethal effects of L-buthionine-SR-Sulfoximine (BSO) with the sulfhydryl-dependent anticancer agents (SHDAA) were investigated in mice. The agents studied included carmustine (BCNU), cyclophosphamide (CTX), doxorubicin (DOX) and melphalan (LPAM). It was shown in normal mice that BSO is nontoxic when given IP or PO at a dose 5 g/kg. In pharmacodynamic studies with two different doses of BSO in CD-1 mice, the liver, kidney and heart demonstrated diurnal variations in thiol content and dose-dependent depression of tissue non-protein sulfhydryl (NPSH) levels. In acute lethal survival studies, mice treated with CTX and BSO exhibited increased lethality with seizures as a possible cause of death. This effect was not seen with BCNU, DOX and LPAM. Evaluations of organ-specific biochemical markers, showed slight elevations in LDH enzyme levels while bone marrow suppression was not enhanced using both in vivo spleen colony assay and in vitro colony forming unit myelotoxicity assays. These results show that the addition of BSO with SHDAA enhances the acute lethality of some agents such as CTX, and may also increase the non-myelosuppressive toxicities of other agents. It is recommended that BSO be used with caution in combination with SHDAA and that monitoring of hepatic enzymes be routinely performed.
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D008811:Mice, Inbred DBA; D013154:Spleen / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000970:Antineoplastic Agents; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione