title: Synthetic matrix metalloproteinase inhibitors inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice.
abstract: OBJECTIVE
  Breast cancer frequently leads to incurable bone metastasis. Essential requirements for the development of bone metastasis are cell-cell and cell-matrix interactions, release of bioactive growth factors and cytokines, and removal of large amounts of bone matrix. Matrix metalloproteinases (MMPs) play an important role in all of these processes, but the possibility of using synthetic MMP inhibitors to decrease bone metastasis has received little attention.
  
  
  METHODS
  In the present study, we tested two general MMP inhibitors, BB-94 and GM6001, in a mouse model of breast cancer-induced bone metastasis.
  
  
  RESULTS
  In a simulation of intervention therapy, mice were inoculated with breast cancer cells, and at the time of diagnosis of osteolytic lesions, the mice were treated for 10 or 15 consecutive days with BB-94 or GM6001, respectively. Both inhibitors reduced the growth of osteolytic lesions by >55% compared with control mice. Next, we simulated prevention therapy by initiating treatment with GM6001 at time of inoculation with cancer cells or 3 days earlier. Assessment of osteolytic lesions 28 days after inoculation showed that, in both cases, the treatment reduced the size of the osteolytic lesions by 60%, compared with that of control mice. Importantly, MMP inhibition also resulted in extension of symptom-free survival in the mice, whether the treatment was initiated at the time of diagnosis of osteolytic lesions or of cancer cell inoculation.
  
  
  CONCLUSIONS
  The present study suggests the potential of synthetic MMP inhibitors as intervention or prevention treatments of breast cancer-induced osteolysis.
authors.affiliation: Center for Clinical and Basic Research, Nordic Bioscience, Herlev/Ballerup, Herlev Hovedgade 207, DK-2730 Herlev, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Winding
authors.forename: Róisín
authors.initials: R
authors.lastname: NicAmhlaoibh
authors.forename: Henriette
authors.initials: H
authors.lastname: Misander
authors.forename: Pernille
authors.initials: P
authors.lastname: Høegh-Andersen
authors.forename: Thomas Levin
authors.initials: TL
authors.lastname: Andersen
authors.forename: Claus
authors.initials: C
authors.lastname: Holst-Hansen
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Heegaard
authors.forename: Niels Taekker
authors.initials: NT
authors.lastname: Foged
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Delaissé
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010014:Osteolysis / Q000517:prevention & control*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat