title: Radiotoxicity of the alpha-emitting bone-seeker 223Ra injected intravenously into mice: histology, clinical chemistry and hematology.
abstract: BACKGROUND
  The alpha-emitter 223Ra, which localizes in osteoblastic active zones, including on skeletal surfaces and in osteoblastic metastases, has recently been introduced as a potential therapeutic agent against skeletal metastases. Here, the adverse effects of high dosages in animals were investigated.
  
  
  METHODS
  Balb/c mice received intravenously (i.v.) either 1250, 2500, or 3750 kBq/kg of dissolved 223RaCl2 and were followed in the initial toxicity phase. At the 4-week end-point, the animals were sacrificed and blood samples were collected to study the effects on clinical chemistry and hematological parameters. Selected organs were weighed and tissue samples examined by microscopy.
  
  
  RESULTS
  Treatment with 223Ra caused a dose-related minimal to moderate depletion of osteocytes and osteoblasts in the bones. Furthermore, a dose-related minimal to marked depletion of the hematopoietic cells in the bone marrow, and a minimal to slight extramedullary hematopoiesis in the spleen and in the mandibular and mesenteric lymph nodes were observed. The LD50 for acute toxicity, defined as death within 4 weeks of receiving the substance, was not reached.
  
  
  CONCLUSIONS
  This study demonstrated that high doses of the bone-seeker 223Ra did not completely inactivate the blood-producing cells. The relatively high tolerance to skeletal alpha doses was probably caused by the surviving pockets of red bone marrow cells beyond the range of alpha particles from the bone surfaces, and the recruitment of peripheral stems cells.
authors.affiliation: Algeta ASA, P.O. Box 54, N-0411 Oslo, Norway. roy.larsen@algeta.com
authors.forename: Roy H
authors.initials: RH
authors.lastname: Larsen
authors.forename: Henrik
authors.initials: H
authors.lastname: Saxtorph
authors.forename: Mikala
authors.initials: M
authors.lastname: Skydsgaard
authors.forename: Jørgen
authors.initials: J
authors.lastname: Borrebaek
authors.forename: Thora J
authors.initials: TJ
authors.lastname: Jonasdottir
authors.forename: Oyvind S
authors.initials: OS
authors.lastname: Bruland
authors.forename: Signe
authors.initials: S
authors.lastname: Klastrup
authors.forename: Robert
authors.initials: R
authors.lastname: Harling
authors.forename: Thomas
authors.initials: T
authors.lastname: Ramdahl
mesh_terms: D000512:Alpha Particles / Q000009:adverse effects*; D000818:Animals; D019963:Clinical Chemistry Tests; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism; D006403:Hematologic Tests; D006410:Hematopoiesis / Q000528:radiation effects*; D006652:Histological Techniques; D007275:Injections, Intravenous; D008198:Lymph Nodes / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000528:radiation effects*; D010011:Osteocytes / Q000528:radiation effects*; D011877:Radionuclide Imaging; D011883:Radium / Q000008:administration & dosage / Q000633:toxicity*; D013154:Spleen / Q000000981:diagnostic imaging / Q000378:metabolism; D013249:Sternum / Q000000981:diagnostic imaging / Q000378:metabolism; D013997:Time Factors
chemical_list: D011883:Radium