title: Treosulfan is an effective inducer of cell death in myeloma cell lines and primary myeloma cells from patients.
abstract: Multiple myeloma is a non-curable haematological disease involving transformed plasma cells. High rates of complete remission can be achieved with autologous peripheral blood stem cell transplantation. Treosulfan is an alkylating substance that has been used in the treatment of ovarian carcinomas for many years. It has a favourable side-effect profile even at high-dose protocols. Thus, the objective of this study was to evaluate the effect of treosulfan on myeloma cells. The treatment of the myeloma cell lines, NCI-H929 and U266, with treosulfan led to apoptosis in both cell lines in a dose- and time-dependent manner. The induction of apoptosis was accompanied by cleavage of caspases -3 and -9 as well as downregulation of the antiapoptotic protein Mcl-1 and upregulation of the inhibitor of cyclin-dependent kinases, p21WAF1/CIP1. Furthermore, 100 micro mol/l treosulfan was capable of inducing cell death in 63.6 +/- 23.9% of primary myeloma cells, whereas treatment with the same concentration of melphalan showed 59.7 +/- 26% cell death. These in vitro concentrations were at least 10-fold lower than achievable plasma levels, even at conventional doses of treosulfan. Our results suggest that treosulfan might be an appropriate candidate for novel treatment protocols for patients with multiple myeloma.
authors.affiliation: Klinikum der Universität München, Medizinische Klinik - Innenstadt, Department of Hematology/Oncology, Laboratory of Molecular Hematology and Oncology, Munich, Germany. geroldmeinhardt@yahoo.de
authors.forename: Gerold
authors.initials: G
authors.lastname: Meinhardt
authors.forename: Farshid
authors.initials: F
authors.lastname: Dayyani
authors.forename: Bernd
authors.initials: B
authors.lastname: Jahrsdörfer
authors.forename: Joachim
authors.initials: J
authors.lastname: Baumgart
authors.forename: Bertold
authors.initials: B
authors.lastname: Emmerich
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmidmaier
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C018404:treosulfan; D020169:Caspases; D002066:Busulfan; D008558:Melphalan