Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients.
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.
Munkelt
Doreen
D
Pediatric Hematology and Oncology, University Hospital, 60596, Frankfurt, Germany.
Koehl
Ulrike
U
Kloess
Stephan
S
Zimmermann
Stefanie-Yvonne
SY
Kalaäoui
Rabiá El
RE
Wehner
Sibylle
S
Schwabe
Dirk
D
Lehrnbecher
Thomas
T
Schubert
Ralf
R
Kreuter
Joerg
J
Klingebiel
Thomas
T
Esser
Ruth
R
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
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