title: Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis.
abstract: BACKGROUND
  Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis.
  
  
  METHODS
  We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. Disease progression was monitored using fluorescence and radiographic imaging and histological analyses. The effect of radium-223 dichloride alone and in combination with doxorubicin or zoledronic acid on survival of mice was analyzed by Kaplan-Meier methods. All statistical tests used were two-sided.
  
  
  RESULTS
  Radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. In an established bone metastasis setting, radium-223 dichloride prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P values < .05). Radium-223 dichloride induced double-strand DNA breaks in cancer cells in vivo. Finally, radium-223 dichloride extended survival as a monotherapy (29.2 days, 95% confidence interval [CI] = 26.6 to 31.8 days, P = .039) and in combination with zoledronic acid (31.4 days, 95% CI = 28.8 to 34.0 days, P = .004) or doxorubicin (31.5 days, 95% CI = 29.5 to 33.5 days, P < .001) compared to the vehicle group (24.9 days, 95% CI = 23.4 to 26.4 days). Similar but even more pronounced effects were observed when radium-223 dichloride was administered in a preventive or micrometastatic setting.
  
  
  CONCLUSIONS
  Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases.
authors.affiliation: Pharmatest Services Ltd, Turku, Finland.
authors.forename: Mari I
authors.initials: MI
authors.lastname: Suominen
authors.forename: Jukka P
authors.initials: JP
authors.lastname: Rissanen
authors.forename: Rami
authors.initials: R
authors.lastname: Käkönen
authors.forename: Katja M
authors.initials: KM
authors.lastname: Fagerlund
authors.forename: Esa
authors.initials: E
authors.lastname: Alhoniemi
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Halleen
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Käkönen
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002100:Cachexia / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D004164:Diphosphonates / Q000008:administration & dosage; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D011868:Radioisotopes / Q000494:pharmacology / Q000627:therapeutic use; D011883:Radium / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004273:DNA, Neoplasm; D004164:Diphosphonates; D007093:Imidazoles; D011868:Radioisotopes; D000077211:Zoledronic Acid; D004317:Doxorubicin; C581106:radium Ra 223 dichloride; D011883:Radium