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 sulfhydril-dependent anticancer agents (SHDAA) were investigated in mice. The agent 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 5g/kg. In pharmacodynamic studies with two different doses of BSO in CD-1 mice, the liver, kidney and heart demonstrated diurinal variations in thiol content and dose-dependent depression of tissue non-protein sulfhydril (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.