title: HDAC inhibitor-loaded bone cement for advanced local treatment of osteosarcoma and chondrosarcoma.
abstract: The treatment of osteosarcoma, especially wide resection, is challenging. An additional local drug therapy after resection using anti-neoplastic bone cement (Polymethylmethacrylate (PMMA)) could help improve the outcome of therapy. In this study, we evaluated the effects of PMMA loaded with valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) on the cell activity of a SaOs-2 cell culture, as well as the elution rate of the drugs out of the bone cement.
  
  
  METHODS
  In our experiments, we used the SaOs-2 osteosarcoma and the SW1353 chondrosarcoma cell line. Bone cement clots (5 g) were prepared and loaded with different drug concentrations of VPA (25 mg and 50 mg) and SAHA (1 mg, 2.5 mg and 5 mg). Two control groups were established, one with a native cement clot, the other with human mesenchymal stem cells, in order to evaluate toxicity on non tumor-cells. Cell activity was measured using an Alamar Blue assay on days 1, 2, 3, 4 and 7. The cement clots were additionally examined in a material testing unit for biomechanical and structural changes.
  
  
  RESULTS
  Tumor cells showed a significant and complete reduction of activity under therapy with VPA and SAHA. Drug release of VPA was extensive between days 0 and 3 and decreased progressively to day 7. Cumulative drug concentration in the medium continuously increased. Biomechanical testing of the cement clots showed no differences in stability and architecture compared to the control group. SaOs-2 and SW1353 cells with medium from native cement clots without drug therapy presented a cell activity of 100% in all groups and during all measurements. Human mesenchymal stem cells were not significantly affected during therapy with VPA and low concentrations of SAHA. In contrast, cell activity of human mesenchymal stem cells was significantly reduced under therapy with higher concentrations of SAHA, with an approximately linear decrease between days 0-3 and a rapidly decreasing activity between days 4-7.
  
  
  CONCLUSIONS
  A local cytotoxic therapy in the treatment of osteosarcoma and chondrosarcoma might improve the rate of metastasis and survival of patients. Our results present an encouraging approach to loading PMMA with anti-neoplastic drugs.
authors.affiliation: Department for Orthopaedic and Trauma Surgery, University Hospital Mannheim, Mannheim, Germany Department of Orthopaedics and Traumatology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Tonak
authors.affiliation: Interdisciplinary Sarcoma Working Group of First Medical Department, University Medical Center Mainz, Mainz, Germany Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Becker
authors.affiliation: Interdisciplinary Sarcoma Working Group of Third Medical Department, University Medical Center Mainz, Mainz, Germany claudine.graf@unimedizin-mainz.de.
authors.forename: Claudine
authors.initials: C
authors.lastname: Graf
authors.affiliation: Department of Orthopaedics and Traumatology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Eckhard
authors.affiliation: Interdisciplinary Sarcoma Working Group of Third Medical Department, University Medical Center Mainz, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.affiliation: Department of Orthopaedics and Traumatology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Pol-Maria
authors.initials: PM
authors.lastname: Rommens
authors.affiliation: Interdisciplinary Sarcoma Working Group of Third Medical Department, University Medical Center Mainz, Mainz, Germany Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, Germany.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wehler
authors.affiliation: Department of Orthopaedics and Traumatology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Proschek
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001696:Biomechanical Phenomena; D001843:Bone Cements / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002813:Chondrosarcoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D019904:Polymethyl Methacrylate / Q000737:chemistry*; D000077337:Vorinostat
chemical_list: D001843:Bone Cements; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D019904:Polymethyl Methacrylate
keywords: Bone cement; HDAC inhibitor; PMMA; SAHA; local therapy; valproic acid