title: Histone deacetylase inhibition sensitizes osteosarcoma to heavy ion radiotherapy.
abstract: BACKGROUND
  Minimal improvements in treatment or survival of patients with osteosarcoma have been achieved during the last three decades. Especially in the case of incomplete tumor resection, prognosis remains poor. Heavy ion radiotherapy (HIT) and modern anticancer drugs like histone deacetylase inhibitors (HDACi) have shown promising effects in osteosarcoma in vitro. In this study, we tested the effect of HIT and the combination of HIT and the HDACi suberoylanilide hydroxamic acid (SAHA) in a xenograft mouse model.
  
  
  METHODS
  Osteosarcoma xenografts were established by subcutaneous injection of KHOS-24OS cells and treated with either vehicle (DMSO), SAHA, HIT or HIT and SAHA. Tumor growth was determined and tumor necrosis, proliferation rate, apoptotic rate as well as vessel density were evaluated.
  
  
  RESULTS
  Here, we show that the combination of HIT and SAHA induced a significant delay of tumor growth through increased rate of apoptosis, increased expression of p53 and p21(Waf1/Cip1), inhibition of proliferation and angiogenesis compared to tumors treated with HIT only.
  
  
  CONCLUSIONS
  HIT and in particular the combination of HIT and histone deacetylase inhibition is a promising treatment strategy in OS and may be tested in clinical trials.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Children's, Hospital of Heidelberg, Heidelberg, Germany. c.blattmann@klinikum-stuttgart.de.|Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. c.blattmann@klinikum-stuttgart.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. c.blattmann@klinikum-stuttgart.de.|Pädiatrie 5, Olgahospital, Kriegsbergstr. 62, 70174, Stuttgart, Germany. c.blattmann@klinikum-stuttgart.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Blattmann
authors.affiliation: Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. oertels2007@aol.de.|Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. oertels2007@aol.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Oertel
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Children's, Hospital of Heidelberg, Heidelberg, Germany. m.thiemann@dkfz-heidelberg.de.|Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. m.thiemann@dkfz-heidelberg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Thiemann
authors.affiliation: Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. anne.dittmar@med.uni-heidelberg.de.|Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. anne.dittmar@med.uni-heidelberg.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Dittmar
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Children's, Hospital of Heidelberg, Heidelberg, Germany. eva.roth@med.uni-heidelberg.de.|Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. eva.roth@med.uni-heidelberg.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Roth
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Children's, Hospital of Heidelberg, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.|National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany. volker.ehemann@med.uni-heidelberg.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany. wilko.weichert@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. wilko.weichert@med.uni-heidelberg.de.|National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. wilko.weichert@med.uni-heidelberg.de.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. p.huber@dkfz-heidelberg.de.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany. albrecht.stenzinger@med.uni-heidelberg.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. juergen.debus@med.uni-heidelberg.de.|Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. juergen.debus@med.uni-heidelberg.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001859:Bone Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D016158:Genes, p53; D063193:Heavy Ion Radiotherapy; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000187:drug effects; D040521:Subcutaneous Tissue; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat