Methotrexate-albumin and aminopterin-albumin effectively prevent experimental acute graft-versus-host disease.
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.
Wolff
Daniel
D
Division of Hematology and Oncology, University of Rostock, Rostock, Germany. daniel.wolff@medizin.uni-rostock.de
Frei
Eva
E
Hofmeister
Nicole
N
Steiner
Beate
B
Kleine
Hans-Dieter
HD
Junghanss
Christian
C
Sievert
Kathrin
K
Terpe
Harald
H
Schrenk
Hans-Hermann
HH
Freund
Mathias
M
Hartung
Gernot
G
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
D007166:Immunosuppressive Agents; D012709:Serum Albumin; D000630:Aminopterin; D008727:Methotrexate