title: Pilot study of intravenous melphalan combined with continuous infusion L-S,R-buthionine sulfoximine for children with recurrent neuroblastoma.
abstract: OBJECTIVE
  To evaluate BSO-mediated glutathione (GSH) depletion in combination with L-PAM for children with recurrent or refractory high-risk neuroblastoma (NB) as a means to enhance alkylator sensitivity.
  
  
  METHODS
  This pilot study (NCI #T95-0092) administered L-S,R-buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m(2)/hr (level 1) or 1.0 g/m(2)/hr (level 2) and melphalan (L-PAM) (15 mg/m(2) bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC.
  
  
  RESULTS
  Thirty two patients received 58 courses of therapy (median 1, range 1-4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady-state concentration (Css) for BSO = 524 ± 207 μM and peak L-PAM concentration = 3.32 ± 1.2 μM. Grade 3-4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm(3)) of a pelvic mass, and three/five patients with >3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/10(5)).
  
  
  CONCLUSIONS
  BSO/L-PAM has activity against recurrent high-risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity.
authors.affiliation: City of Hope National Medical Center, Department of Pediatrics, Duarte, California.
authors.forename: Clarke P
authors.initials: CP
authors.lastname: Anderson
authors.affiliation: Department of Pediatrics, University of California School of Medicine, San Francisco, California.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: John P
authors.initials: JP
authors.lastname: Perentesis
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Neglia
authors.affiliation: Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Beth
authors.initials: B
authors.lastname: Hasenauer
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.affiliation: Cancer Center and Departments of Cell Biology & Biochemistry, Pediatrics and Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy*; D010865:Pilot Projects
chemical_list: D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan
keywords: glutathione; melphalan; neuroblastoma; reactive oxygen species