title: Methotrexate-albumin and aminopterin-albumin effectively prevent experimental acute graft-versus-host disease.
abstract: BACKGROUND
  During the last several years, major progress has been made in developing targeted chemotherapy using cytotoxic drugs covalently bound to human serum albumin (HSA). We explored the activity of two antifolates methotrexate (MTX) and aminopterin (AMPT) bound to HSA in prophylaxis and treatment of experimental acute graft-versus-host disease (aGVHD).
  
  
  METHODS
  In all, 113 female F1 hybrid BN/Lew-rats were irradiated with 8.2 Gy (n=103) or 9.9 Gy (n=10). One day after irradiation each rat received 4 x 10 bone marrow cells and 1.5 x 10 spleen T-cells from female Lew-rats. GVHD prophylaxis consisted of MTX-HSA 2 mg/kg (n=25), MTX-HSA 0.5 mg/kg (n=8), AMPT-HSA 0.65 mg/kg (n=8), MTX 0.5 mg/kg (n=17), or native HSA (n=39) given intraperitoneally (IP) on days 0, 4, 8, and 12. Treatment of aGVHD consisted of MTX-HSA 2 mg/kg (n=8) or AMPT-HSA 0.5 mg/kg (n=8) given intraperitoneally at the time of onset of aGVHD and subsequently every fourth day (a total of four doses).
  
  
  RESULTS
  All animals receiving native HSA developed lethal aGVHD. Prophylactic treatment with MTX-HSA 2 mg/kg prevented aGVHD in 18 of 25 animals and in 6 of 8 receiving AMPT-HSA. In contrast, five out of nine rats receiving free MTX died due to aGVHD. The survival rates in the prophylactic MTX-HSA 2 mg/kg and AMPT-HSA groups were significantly higher compared to the MTX and control groups (P<0.05), while non hematologic toxicity of MTX-HSA was not detectable. AMPT-HSA at a dose of 0.65 mg/kg as well as MTX at a dose of 0.5 mg/kg were associated with temporary weight loss and lethargy.
  
  
  CONCLUSIONS
  The albumin conjugates MTX-HSA and AMPT-HSA effectively prevent experimental aGVHD.
authors.affiliation: Division of Hematology and Oncology, University of Rostock, Rostock, Germany. daniel.wolff@medizin.uni-rostock.de
authors.forename: Daniel
authors.initials: D
authors.lastname: Wolff
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.forename: Nicole
authors.initials: N
authors.lastname: Hofmeister
authors.forename: Beate
authors.initials: B
authors.lastname: Steiner
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Kleine
authors.forename: Christian
authors.initials: C
authors.lastname: Junghanss
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sievert
authors.forename: Harald
authors.initials: H
authors.lastname: Terpe
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Schrenk
authors.forename: Mathias
authors.initials: M
authors.lastname: Freund
authors.forename: Gernot
authors.initials: G
authors.lastname: Hartung
mesh_terms: D000208:Acute Disease; D000630:Aminopterin / Q000008:administration & dosage*; D000818:Animals; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D012709:Serum Albumin / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D012709:Serum Albumin; D000630:Aminopterin; D008727:Methotrexate