Toward a myeloablative regimen with clinical potential: II. Treosulfan induces specific skin graft tolerance across haploidentical MHC barriers.
Treosulfan is a water-soluble structural analog of busulfan, acting as a prodrug of alkylating epoxide species. It does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has a limited organ toxicity. It is mainly indicated for the treatment of patients with ovarian cancer. In the present study, we report that permanent donor-specific tolerance and stable mixed multilineage chimerism can successfully be achieved across haploidentical MHC barriers when Treosulfan is administered in combination with anti-T-cell mAb and T-cell-depleted donor bone marrow cells. Furthermore, we show that less T-cell suppression is required when Treosulfan is included in the conditioning regimen. In conclusion, Treosulfan is a well-tolerated myeloablative agent with a low toxicity, and is a promising candidate drug for conditioning prior to bone marrow transplantation.
van Pel
M
M
Laboratory for Vaccine Research, National Institute of Public Health and the Environment (RIVM), A van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands.
van Breugel
D W J G
DW
Vos
W
W
Ploemacher
R E
RE
Boog
C J P
CJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D006238:Haploidy; D007108:Immune Tolerance / Q000187:drug effects*; D066298:In Vitro Techniques; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019653:Myeloablative Agonists / Q000494:pharmacology*; D016038:Skin Transplantation; D018183:Transplantation Chimera; D019172:Transplantation Conditioning
D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D017252:CD3 Complex; D019653:Myeloablative Agonists; C018404:treosulfan; D002066:Busulfan