Preclinical analysis of treosulfan in combination with total body irradiation as conditioning regimen prior to bone marrow transplantation in rats.
Treosulfan (Treo) and total body irradiation (TBI) demonstrate a high therapeutic activity in treatment of acute leukemia and lymphoma. We investigated the combination of Treo and TBI prior to bone marrow transplantation (BMT) in rats. Female Lewis rats were treated with Treo on 3 consecutive days followed by TBI with either 5 Gy (n = 28) or 7.5 Gy (n = 48). After conditioning animals received 4 x 10E7 bone marrow cells (BC) from female Lewis rats. Additional 16 rats were transplanted with 4 x 10E7 BC and 1.5 x 10E7 spleen T-cells from female Brown-Norway (BN) rats. Animals were examined daily for clinical signs and toxicity was investigated by necropsy and histology in all animals. Gastrointestinal toxicity was the dose-limiting factor of Treo in combination with TBI. The highest tolerable dose of Treo in combination with 7.5 Gy TBI was 3 x 0.5 g/kg and the highest tolerable dose of Treo in combination with 5 Gy TBI was 3 x 0.6 g/kg. Allogeneic BMT from BN donors resulted in engraftment and survival of 12 out of 16 animals. Gastrointestinal toxicity is the dose-limiting factor in the treatment with Treo and TBI. Furthermore, Treo possesses certain characteristics of a radiosensitizer.
Sender
Vicky
V
Department of Hematology and Oncology, Department of Medicine, University of Rostock, Rostock, Germany.
Hofmeister-Mielke
Nicole
N
Sievert
Kathrin
K
Teifke
Jens Peter
JP
Vogel
Heike
H
Baumgart
Joachim
J
Pichlmeier
Uwe
U
Freund
Mathias
M
Casper
Jochen
J
Wolff
Daniel
D
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology; D003131:Combined Modality Therapy / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D019172:Transplantation Conditioning / Q000379:methods; D014916:Whole-Body Irradiation / Q000379:methods
C018404:treosulfan; D002066:Busulfan