title: Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing's sarcoma via inhibition of cell migration.
abstract: BACKGROUND
  Ewing's sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties.
  
  
  METHODS
  Invasion assays were performed in vitro in Boyden's chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology.
  
  
  RESULTS
  ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and -9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases.
  
  
  CONCLUSIONS
  These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Odri
authors.forename: Pui-Pui
authors.initials: PP
authors.lastname: Kim
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.forename: Séverine
authors.initials: S
authors.lastname: Battaglia
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: François
authors.initials: F
authors.lastname: Gouin
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France. francoise.redini@univ-nantes.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9