title: Specific marrow ablation before marrow transplantation using an aminophosphonic acid conjugate 166Ho-EDTMP.
abstract: 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.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: P A
authors.initials: PA
authors.lastname: Brown
authors.forename: B M
authors.initials: BM
authors.lastname: Sandmaier
authors.forename: R
authors.initials: R
authors.lastname: Storb
authors.forename: D R
authors.initials: DR
authors.lastname: Fisher
authors.forename: H M
authors.initials: HM
authors.lastname: Shulman
authors.forename: T C
authors.initials: TC
authors.lastname: Graham
authors.forename: F G
authors.initials: FG
authors.lastname: Schuening
authors.forename: H J
authors.initials: HJ
authors.lastname: Deeg
authors.forename: J A
authors.initials: JA
authors.lastname: Bianco
mesh_terms: 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
chemical_list: D002614:Chelating Agents; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D011868:Radioisotopes; D006695:Holmium