BACKGROUND: Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor 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 with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value). METHODS: Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO. RESULTS: Continuous-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 pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections. CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.
BACKGROUND: Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor 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 with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value). METHODS: Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO. RESULTS: Continuous-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 pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections. CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumorglutathione.
Authors: Mario Faundez; Laura Pino; Paula Letelier; Carla Ortiz; Rodrigo López; Claudia Seguel; Jorge Ferreira; Mario Pavani; Antonio Morello; Juan Diego Maya Journal: Antimicrob Agents Chemother Date: 2005-01 Impact factor: 5.191
Authors: J E Chang; P M Voorhees; J M Kolesar; H G Ahuja; F A Sanchez; G A Rodriguez; K Kim; J Werndli; H H Bailey; B S Kahl Journal: Hematol Oncol Date: 2009-03 Impact factor: 5.271
Authors: David M Mattson; Iman M Ahmad; Disha Dayal; Arlene D Parsons; Nukhet Aykin-Burns; Ling Li; Kevin P Orcutt; Douglas R Spitz; Kenneth J Dornfeld; Andrean L Simons Journal: Free Radic Biol Med Date: 2008-10-18 Impact factor: 7.376