title: In vivo efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid in combination with radiotherapy in a malignant rhabdoid tumor mouse model.
abstract: OBJECTIVE
  Histone deacetylase inhibitors are promising new substances in cancer therapy and have also been shown to sensitize different tumor cells to irradiation (XRT). We explored the effect as well as the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) in vivo in a malignant rhabdoid tumor (MRT) mouse model.
  
  
  METHODS
  Potential radiosensitization by SAHA was assessed in MRT xenografts by analysis of tumor growth delay, necrosis (HE), apoptosis (TUNEL), proliferation (ki-67) and γH2AX expression as well as dynamic 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG -PET) after treatment with either SAHA alone, single-dose (10 Gy) or fractionated XRT (3 × 3Gy) solely as well as in combination with SAHA compared to controls.
  
  
  RESULTS
  SAHA only had no significant effect on tumor growth. Combination of SAHA for 8 days with single-dose XRT resulted in a higher number of complete remissions, but failed to prove a significant growth delay compared to XRT only. In contrast fractionated XRT plus SAHA for 3 weeks did induce significant tumor growth delay in MRT-xenografts. The histological examination showed a significant effect of XRT in tumor necrosis, expression of Ki-67, γH2AX and apoptosis. SAHA only had no significant effect in the histological examination. Comparison of xenografts treated with XRT and XRT plus SAHA revealed a significantly increased γH2AX expression and apoptosis induction in the mice tumors after combination treatment with single-dose as well as fractionated XRT. The combination of SAHA with XRT showed a tendency to increased necrosis and decrease of proliferation compared to XRT only, which, however, was not significant. The 18F-FDG-PET results showed no significant differences in the standard uptake value or glucose transport kinetics after either treatment.
  
  
  CONCLUSIONS
  SAHA did not have a significant effect alone, but proved to enhance the effect of XRT in our MRT in vivo model.
authors.affiliation: Department of Radiation Oncology, University of Heidelberg, INF 600, 69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Thiemann
authors.forename: Susanne
authors.initials: S
authors.lastname: Oertel
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Marc
authors.initials: M
authors.lastname: Bischof
authors.forename: Klaus-J
authors.initials: KJ
authors.lastname: Weber
authors.forename: Ramon Lopez
authors.initials: RL
authors.lastname: Perez
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.forename: Claudia
authors.initials: C
authors.lastname: Battmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011878:Radiotherapy; D018335:Rhabdoid Tumor / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011838:Radiation-Sensitizing Agents; D000077337:Vorinostat