EDTMP Research Articles

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.

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.

Simultaneous study of the biodistribution of radio-yttrium complexed with EDTMP and citrate ligands in tumour-bearing rats

The influence of the ligands ethylenediaminetetramethylene phosphonic acid (EDTMP) and citrate (CIT) on the biodistribution of radio-yttrium in rats bearing a DS-carcinosarcoma was compared. 88Y-EDTMP and 87Y-CIT were i.v. injected into the same animals. Faster blood clearance and higher renal excretion were observed for the EDTMP-ligand. Of high practical interest is the reduced liver uptake of radio-yttrium (by one order of magnitude) with the EDTMP complex. Since bone and tumour accumulation is only weakly influenced, high tumour-to-liver ratios (up to 14) were observed. We propose to use EDTMP or similar complex ligands for liver blocking when radionuclides like 90Y, 169Yb, 225Ac or other group 3 elements are to be applied in endoradionuclide therapy technique.

Kinetics and mechanism of the oxidation of some chelating agents by perbenzoic acids

The kinetics of the N-oxidation of ethylenediaminetetra-acetic acid, diethylenetriaminepenta-acetic acid, and ethylenediaminetetramethylenephosphonic acid by substituted perbenzoic acids has been studied. The dependence of the second-order rate constant on the nature of the peracid, pH, the basicity of the nitrogen atom of the chelating agent, and the temperature of the reaction is consistent with a mechanism involving nucleophilic attack of the nitrogen of the chelating agent on the outer peroxidic oxygen of the peracid. The kinetic data is of importance in assessing how added chelators suppress the metal-ion catalysed reactions of peracids.

Persistence of Secondary Spongiosa in Three Calves

ical application of 113mIn-DTPMP and 'I3'In-EDTMP. Chung Hua I Hsueh Tsa Chih (Peking) 60:200-203,1980 5 Meyer JL, Nancollas GH: The influence of multidentate organic phosphonates on crystal growth of hydroxyapatite. Calcif Tissue Res 13:295-303, 1973 6 Miller SC, Jee WSS, Woodbury DM, Kemp J W Effects of N,N,N',N'-ethylenediaminetetramethylene phosphonic acid and 1 -hydroxyethylidene1,l -bisphosphonic acid on calcium absorption, plasma calcium, longitudinal bone growth, and bone histology in the growing rat. Toxicol Appl Pharmacol77:230-239, 1985 7 Raisz LG: Direct effects of vitamin D and its metabolites on skeletal tissue. In: Clinics in Endocrinology and Metabolism, ed. Avioli LV and Raisz LG, vol. 9, pp. 27-41. WB Saunders Co, Philadelphia, PA, 1980 8 Schenk RK, Olah AJ: What is osteomalacia? In: Advances in Experimental and Molecular Biology, ed. Massry SG, Ritz E, and John H, vol. 128, pp. 549-562. Plenum Press, New York, N Y , 1979 9 Srivastava SC, Richards P, Som P, Meinken G, Atkins HL, Sewatkar A, Ku TH: Ruthenium-97 labeled compoundsa new class of radiopharmaceuticals. Front Nucl Med 2:123-133, 1978 10 Trechsel U, Schenk R, Bonjour JP, Russell RGG, Fleisch H: Relation between bone mineralization, Ca absorption, and plasma Ca in phosphonate-treated rats. Am J Physiol 232:298-305, 1977

Effects of N,N,N′,N′-ethylenediaminetetramethylene phosphonic acid on cortical bone remodeling in the adult dog

Phosphonic acids are of interest because of their potential usefulness in the treatment of disorders of bone and mineral metabolism, as a treatment for dental calculus, and as skeletal imaging agents. The effects of oral doses of N,N,N′,N′-ethylenediaminetetramethylene phosphonic acid (EDITEMPA) on cortical bone remodeling and histology of adult dogs were determined. After treatment for 3 and 6 months, there were dose-related changes observed in cortical bone as measured using histomorphometric methods. With higher doses, EDITEMPA treatment resulted in the accumulation of osteoid due to impaired or delayed mineralization of bone. There was an increased mineralized and osseous tissue porosity suggesting an early increase in bone resorption perhaps due to an increased activation of bone remodeling.

Effects of N,N,N′,N′-ethylenediaminetetramethylene phosphonic acid and 1-hydroxyethylidene-1,1-bisphosphonic acid on calcium absorption, plasma calcium, longitudinal bone growth, and bone histology in the growing rat

Phosphonate compounds are of considerable interest because of their effects on biological mineralization and mineral metabolism. The effects of graded doses given parenterally or orally of N,N,N′,N′-ethylenediamine tetramethylene phosphonic acid (EDITEMPA) on calcium absorption, plasma calcium, endochondral bone elongation, and osseous tissue histology of rats were determined. In some experiments 1-hydroxyethylidene-1,1-bisphosphonic acid (HEBP) was included for comparison. Given sc for 7 days, EDITEMPA caused dose-related decreases in net weight gain, intestinal calcium absorption, and longitudinal bone growth. There were also increases in total plasma calcium concentrations and excess osteoid accumulation in bone. When EDITEMPA was given po for 7, 28, or 90 days, few changes in osseous tissues were observed and then only at the highest dose (333 mg/kg/day). An equivalent dose of HEBP caused substantial changes in osseous tissues and calcium parameters.

Ethylene-diamine-tetra(methylene-phosphonic) Acid

SINCE the publication by Schwarzenbach et al.1 of the relatively high degree of calcium binding by N-methylene-phosphonic-imino-diacetic acid, it seems that the phosphonate group may be quite as effective as the carboxylate group in chelating agents. An attempt to prepare ethylene-diamine-tetra-methylene-phosphonic acid (EDPA) was therefore indicated because of its similarity to ethylene-diamine-tetra-acetic acid (EDTA). Although the preparation of this and similar compounds has been reported by Bersworth2, the present communication gives quantitative information of the affinity of the ethylene-diamine-tetra-methylene-phosphonic acid anion for hydrogen ions and metal ions.