title: Histone deacetylase (HDAC) 1 and 2 expression and chemotherapy in gastric cancer.
abstract: BACKGROUND
  Histone deacetylases (HDACs) modulate chromatin and may influence the effect of DNA-damaging drugs. We investigated HDAC1 and -2 expression in gastric carcinomas (GCs) for an association of patient outcome with conventional neoadjuvant chemotherapy. In vitro, HDAC inhibitors were evaluated as alternative treatment options.
  
  
  METHODS
  HDAC1/2 expression was analyzed immunohistochemically in 127 pretherapeutic biopsy samples of neoadjuvant (platinum/5-fluorouracil) chemotherapy-treated GC patients and correlated with response and overall survival (OS). Chemosensitivity of four GC cell lines to cisplatin and the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and valproic acid was determined by XTT assays. Efficiencies of combined drug schedules were analyzed.
  
  
  RESULTS
  High expression of HDAC1/2 was found in 69 (54%) of 127 and 108 (85%) of 127 carcinomas, respectively, and was not associated with response or OS. In patients whose disease responded to therapy, high HDAC1 expression was associated with worse OS (P = 0.005). In cell lines, sequential treatment with SAHA and cisplatin showed synergistic effects irrespective of the initial cisplatin sensitivity.
  
  
  CONCLUSIONS
  HDAC1 and -2 expression is not suitable to predict response or survival for neoadjuvant-treated GC patients, but HDAC1 expression may be used for risk stratification in patients whose disease responds to therapy. Sequential treatment with SAHA and cisplatin may represent an alternative treatment option for GC patients.
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mutze
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Karen
authors.initials: K
authors.lastname: Becker
authors.forename: Katja
authors.initials: K
authors.lastname: Ott
authors.forename: Alexander
authors.initials: A
authors.lastname: Novotny
authors.forename: Birgit
authors.initials: B
authors.lastname: Luber
authors.forename: Alexander
authors.initials: A
authors.lastname: Hapfelmeier
authors.forename: Martin
authors.initials: M
authors.lastname: Göttlicher
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D017322:Clinical Trials, Phase II as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000627:therapeutic use; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D014635:Valproic Acid; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D002945:Cisplatin; D005472:Fluorouracil