title: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
abstract: BACKGROUND
  The cytidine nucleoside analogs azacitidine (AZA) and decitabine (DAC) are used for the treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Few non-clinical studies have directly compared the mechanisms of action of these agents in a head-to-head fashion, and the agents are often viewed as mechanistically similar DNA hypomethylating agents. To better understand the similarities and differences in mechanisms of these drugs, we compared their in vitro effects on several end points in human AML cell lines.
  
  
  RESULTS
  Both drugs effected DNA methyltransferase 1 depletion, DNA hypomethylation, and DNA damage induction, with DAC showing equivalent activity at concentrations 2- to 10-fold lower than AZA. At concentrations above 1 microM, AZA had a greater effect than DAC on reducing cell viability. Both drugs increased the sub-G1 fraction and apoptosis markers, with AZA decreasing all cell cycle phases and DAC causing an increase in G2-M. Total protein synthesis was reduced only by AZA, and drug-modulated gene expression profiles were largely non-overlapping.
  
  
  CONCLUSIONS
  These data demonstrate shared mechanisms of action of AZA and DAC on DNA-mediated markers of activity, but distinctly different effects in their actions on cell viability, protein synthesis, cell cycle, and gene expression. The differential effects of AZA may be mediated by RNA incorporation, as the distribution of AZA in nucleic acid of KG-1a cells was 65:35, RNA:DNA.
authors.affiliation: Celgene Corporation, San Francisco, California, United States of America.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hollenbach
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Nguyen
authors.forename: Helen
authors.initials: H
authors.lastname: Brady
authors.forename: Michelle
authors.initials: M
authors.lastname: Williams
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Ning
authors.forename: Normand
authors.initials: N
authors.lastname: Richard
authors.forename: Leslie
authors.initials: L
authors.lastname: Krushel
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Aukerman
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: MacBeth
mesh_terms: D000208:Acute Disease; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D014176:Protein Biosynthesis / Q000187:drug effects*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C411744:DMAP1 protein, human; D012097:Repressor Proteins; D000077209:Decitabine; D001374:Azacitidine