title: Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.
abstract: OBJECTIVE
  The cytidine analogs 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase 1 (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application.
  
  
  METHODS
  Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity, and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated patients with MDS (n = 90) and cytarabine-treated patients with acute myeloid leukemia (AML) (n = 76).
  
  
  RESULTS
  By high-performance liquid chromatography (HPLC), plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females than in males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared with high S-phase fraction disease (e.g., MDS vs. AML), because in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female patients with MDS treated with 5-azacytidine/decitabine.
  
  
  CONCLUSIONS
  Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.
authors.affiliation: Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Reda Z
authors.initials: RZ
authors.lastname: Mahfouz
authors.forename: Ania
authors.initials: A
authors.lastname: Jankowska
authors.forename: Quteba
authors.initials: Q
authors.lastname: Ebrahem
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Gu
authors.forename: Valeria
authors.initials: V
authors.lastname: Visconte
authors.forename: Ali
authors.initials: A
authors.lastname: Tabarroki
authors.forename: Pramod
authors.initials: P
authors.lastname: Terse
authors.forename: Joseph
authors.initials: J
authors.lastname: Covey
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chan
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Ling
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Engelke
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Ramon
authors.initials: R
authors.lastname: Tiu
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciejewski
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives; D003561:Cytarabine / Q000008:administration & dosage; D003562:Cytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D003561:Cytarabine; D003562:Cytidine; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D003564:Cytidine Deaminase; D001374:Azacitidine