Myeloablative and immunosuppressive properties of treosulfan in mice.
OBJECTIVE
Treosulfan is a prodrug with a specific clinical activity in ovarian carcinoma and other solid tumors. Due to its myeloablative and immunosuppressive effects, its use in conditioning regimens prior to allogeneic stem cell treatment (SCT) has been proposed. In the present preclinical study, myeloablative as well as immunosuppressive properties of treosulfan were compared with those of busulfan and cyclophosphamide.


METHODS
Three groups of BALB/c mice were treated with treosulfan, cyclophosphamide, or busulfan at sublethal doses that maintained survival without bone marrow support. The control group was left untreated. At different intervals, colony-forming unit granulocyte macrophage assay was performed on marrow cells. Additionally, immunological analyses were performed using spleen cells.


RESULTS
We found that treosulfan and busulfan induced a high and persisting degree of myeloablation, as compared with cyclophosphamide. Moreover, treosulfan was more effective in depletion of splenic B and T cells in comparison with busulfan and cyclophosphamide. Furthermore, T cells isolated from the spleens of treosulfan- or busulfan-treated mice were not responsive to allogeneic cells compared with that observed in controls and cyclophosphamide-treated mice. Treatment with treosulfan induced only interleukin-2 production in spleen cells for a short time and had no significant effect on synthesis of tumor necrosis factor-alpha and/or interferon-gamma as compared with that observed in splenic T cells isolated from mice treated with either busulfan or cyclophosphamide.


CONCLUSIONS
Our findings suggest that treosulfan possesses both myeloablative and immunosuppressive properties and may be used as a single agent for conditioning prior to bone marrow transplantation.
Sjöö
Fredrik
F
Laboratory of Hematology, Karolinska Hematology Center, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Hassan
Zuzana
Z
Abedi-Valugerdi
Manuchehr
M
Griskevicius
Laimonas
L
Nilsson
Christina
C
Remberger
Mats
M
Aschan
Johan
J
Concha
Hernan
H
Gaughan
Una
U
Hassan
Moustapha
M
D000818:Animals; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology; D002452:Cell Count; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
D016207:Cytokines; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; C018404:treosulfan; D002066:Busulfan