title: Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers.
abstract: OBJECTIVE
  5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers.
  
  
  METHODS
  5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 mug/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m(2) and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them.
  
  
  RESULTS
  Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m(2) of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m(2) of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed.
  
  
  CONCLUSIONS
  The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m(2) for 5-AZA in patients with advanced malignancies.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), Division of Cancer Medicine and Quantitative Sciences, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Fadi
authors.initials: F
authors.lastname: Braiteh
authors.forename: Andres O
authors.initials: AO
authors.lastname: Soriano
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.forename: Marcella M
authors.initials: MM
authors.lastname: Johnson
authors.forename: Leandro De Padua
authors.initials: Lde P
authors.lastname: Silva
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Stefanie
authors.initials: S
authors.lastname: Alexander
authors.forename: Johannes
authors.initials: J
authors.lastname: Wolff
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage*; D002648:Child; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: D014635:Valproic Acid; D001374:Azacitidine