title: Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients.
abstract: OBJECTIVE
  The alkylating agent treosulfan exerts a high cytotoxic activity against various malignant cells. Due to limited non-hematological toxicity, treosulfan might be a promising compound in myeloablative therapy for hematopoietic transplantation in children. Since in vitro data regarding the activity of treosulfan against childhood leukemic cells are limited, we compared the effect of treosulfan and busulfan against pediatric leukemic and non-malignant cells.
  
  
  METHODS
  Both agents were tested alone and in combination with fludarabine by means of the MTT and/or a five color-flow cytometric assay. Moreover, the induction of apoptosis by treosulfan was investigated via regulation of the proteinase caspase 3.
  
  
  RESULTS
  Treosulfan was more active against leukemic cells of 20 children as well as against 3 leukemia-derived cell lines than busulfan, with increasing IC50 values from initial diagnosis to relapse. Overall purified stem cells were most sensitive, followed by CD56+CD3- NK and CD3+ T cells. The combination of treosulfan with fludarabine resulted in a synergistic effect against leukemic cells. In malignant cells, treosulfan induced rapid cell apoptosis measured by the activation of the centrally proteinase caspase 3.
  
  
  CONCLUSIONS
  Our results indicate that treosulfan has activity against pediatric leukemic cells, myeloablative potential and immunosuppressive properties suitable for conditioning regimen in childhood malignancies.
authors.affiliation: Pediatric Hematology and Oncology, University Hospital, 60596, Frankfurt, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Munkelt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Koehl
authors.forename: Stephan
authors.initials: S
authors.lastname: Kloess
authors.forename: Stefanie-Yvonne
authors.initials: SY
authors.lastname: Zimmermann
authors.forename: Rabiá El
authors.initials: RE
authors.lastname: Kalaäoui
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wehner
authors.forename: Dirk
authors.initials: D
authors.lastname: Schwabe
authors.forename: Thomas
authors.initials: T
authors.lastname: Lehrnbecher
authors.forename: Ralf
authors.initials: R
authors.lastname: Schubert
authors.forename: Joerg
authors.initials: J
authors.lastname: Kreuter
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.forename: Ruth
authors.initials: R
authors.lastname: Esser
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D013778:Tetrazolium Salts; D013844:Thiazoles; C018404:treosulfan; D053148:Caspase 3; C022616:thiazolyl blue; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine