Specific marrow ablation before marrow transplantation using an aminophosphonic acid conjugate 166Ho-EDTMP.
166Holmium ethylenediaminetetramethylene phosphonic acid (166Ho-EDTMP) is a short-lived beta-emitting radionuclide complexed to an aminophosphonate ligand that we have investigated in a canine model as a potential agent for specific marrow ablation before marrow transplantation. After intravenous injections, 166Ho-EDTMP distributed principally to bone and after 24 hours the concentrations of 166Ho-EDTMP in bone were more than 200-fold higher than in any other organ. Increasing dosages of 166Ho-EDTMP led to increasingly prolonged and severe myelosuppression, but myeloablation was not achieved. Histologic examination of recovering animals suggested that the spleen may have acted as a reservoir for circulatory hematopoietic precursors. Four splenectomized animals administered 20 to 30 mCi/kg 166Ho-EDTMP without marrow transplantation died with marrow aplasia, while four splenectomized animals administered similar dosages of 166Ho-EDTMP followed by autologous transplantation recovered. The dose-limiting toxicity of 166Ho-EDTMP appeared to be marrow stromal damage resulting in myelofibrosis, which was reversible. These results suggest that 166Ho-EDTMP can be used to specifically ablate marrow function before marrow transplantation.
Appelbaum
F R
FR
Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
Brown
P A
PA
Sandmaier
B M
BM
Storb
R
R
Fisher
D R
DR
Shulman
H M
HM
Graham
T C
TC
Schuening
F G
FG
Deeg
H J
HJ
Bianco
J A
JA
D000818:Animals; D001769:Blood / Q000000981:diagnostic imaging; D001853:Bone Marrow / Q000528:radiation effects*; D016026:Bone Marrow Transplantation; D001842:Bone and Bones / Q000000981:diagnostic imaging; D002614:Chelating Agents / Q000493:pharmacokinetics; D004285:Dogs; D006410:Hematopoiesis / Q000528:radiation effects; D006695:Holmium; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics; D011868:Radioisotopes; D011877:Radionuclide Imaging; D013156:Splenectomy
D002614:Chelating Agents; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D011868:Radioisotopes; D006695:Holmium