PHASE-I STUDY OF CONTINUOUS-INFUSION L-S,R-BUTHIONINE SULFOXIMINE WITH INTRAVENOUS MELPHALAN

Background: Increased intracellular glutathione has long been associat ed with tumor cell resistance to various cytotoxic agents, An inhibito r of glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and in vivo, We performed a phase I study of BSO administered wi th the anticancer drug melphalan to determine the combination's safety /tolerability and to determine clinically whether BSO produced the des ired biochemical end point of glutathione depletion (<10% of pretreatm ent value), Methods: Twenty-one patients with advanced cancers receive d an initial 30-minute infusion of BSO totaling 3.0 g/m(2) and immedia tely received a continuous infusion of BSO on one of the following sch edules: 1) 0.75 g/m(2) per hour for 24 hours (four patients); 2) the s ame dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m(2) per hour for 48 hours (three patients), During week 1, the patients received BSO alone; during week s 2 or 3, they received BSO plus melphalan (15 mg/m(2)); thereafter, t he patients received BSO plus melphalan every 4 weeks, Glutathione con centrations in peripheral blood lymphocytes were determined for all pa tients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specime ns taken before, during, and after continuous-infusion BSO, Results: C ontinuous-infusion BSO alone produced minimal toxic effects, although BSO plus melphalan produced occasional severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2), This treatment also produced consistent, profound glutathione depletion (<10% of pret reatment value), The degree of glutathione depletion in peripheral lym phocytes was considerably less than that observed in tumor sections, C onclusions: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.