title: Effects of valproic acid in combination with S-1 on advanced pancreatobiliary tract cancers: clinical study phases I/II.
abstract: OBJECTIVE
  Pancreatobiliary tract cancers are amongst the most aggressive human cancers. Histone deacetylase (HDAC) is well-known to be associated with tumorigenesis through epigenetic regulation and its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. We conducted a clinical trial of combination therapy using valproic acid (VPA, a HDACI) and S-1, which is an oral fluoropyrimidine derivative consisting of 5-fluorouracil.
  
  
  METHODS
  Patients with advanced pancreatobiliary tract cancers were eligible for this clinical trial. Twelve patients, in whom a curative operation was not feasible, were enrolled in the study. Patients received S-1 orally at a daily dose of 80 mg/m(2) for 28 days, followed by a 14-day recovery period. They also received VPA orally at a total daily dose of 15 mg/kg, twice daily.
  
  
  RESULTS
  One patient had partial response (PR); ten patients were recorded with stable disease (SD); and one patient showed progressive disease (PD). Eight patients had clinically significant drug-related adverse events. The most frequent adverse events were platelet depletion and fatigue. Grade 3/4 adverse events, including anemia and platelet depletion, were observed. Significant increases in blood concentrations of VPA were confirmed 2 and 4 weeks after VPA administration.
  
  
  CONCLUSIONS
  Combination therapy of VPA and S-1 for patients with pancreatobiliary tract cancers had a manageable safety profile and preliminary antitumor activity.
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Iwahashi
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Utsunomiya
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Imura
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morine
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ikemoto
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Arakawa
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Ishikawa
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan mitsuo.shimada@tokushima-u.ac.jp.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D004338:Drug Combinations; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010094:Oxonic Acid / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D005641:Tegafur / Q000008:administration & dosage; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D014635:Valproic Acid; D006655:Histone Deacetylases
keywords: Pancreatic cancer; cholangiocarcinoma; clinical trial; histone deacetylase (HDAC); histone deacetylase inhibitor (HDACI); valproic acid (VPA)