title: Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan.
abstract: 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.
authors.affiliation: Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA. hhbailey@facstaff.wisc.edu
authors.forename: H H
authors.initials: HH
authors.lastname: Bailey
authors.forename: G
authors.initials: G
authors.lastname: Ripple
authors.forename: K D
authors.initials: KD
authors.lastname: Tutsch
authors.forename: R Z
authors.initials: RZ
authors.lastname: Arzoomanian
authors.forename: D
authors.initials: D
authors.lastname: Alberti
authors.forename: C
authors.initials: C
authors.lastname: Feierabend
authors.forename: D
authors.initials: D
authors.lastname: Mahvi
authors.forename: J
authors.initials: J
authors.lastname: Schink
authors.forename: M
authors.initials: M
authors.lastname: Pomplun
authors.forename: R T
authors.initials: RT
authors.lastname: Mulcahy
authors.forename: G
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005978:Glutathione / Q000097:blood / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan