title: Role of cytidine deaminase in toxicity and efficacy of nucleosidic analogs.
abstract: BACKGROUND
  Nucleosidic analogs such as pyrimidine and purine derivatives are mainstay in the field of treating cancers, both in adults and in children. All these drugs act as antimetabolite compounds, that is, they interfere with the ability of cancer cells to synthesize the nucleosides or the nucleotides necessary for proliferation and progression. As with most cytotoxics, maintaining patients in their therapeutic window is challenging, and predicting changes in drug exposure is critical to ensure an optimal efficacy/toxicity balance.
  
  
  METHODS
  Among the antimetabolites, a small but widely prescribed number of drugs (i.e., gemcitabine, capecitabine, cytarabine, azacytidine) share a same metabolic pattern driven by a liver enzyme, cytidine deaminase (CDA), coded by a gene displaying several genetic and epigenetic polymorphisms. Consequently, CDA activity is erratic, ranging from deficient to ultra-rapid deaminator patients, with subsequent impact on drug pharmacokinetics and pharmacodynamics eventually. This review provides an update on the variety of clinical studies and case-reports investigating on CDA status as a marker for clinical outcome in cancer patients treated with nucleosidic analogs.
  
  
  CONCLUSIONS
  Whereas sorting patients on the basis of their CDA genotype remains tricky because of unclear genotype-to-phenotype relationships, developing functional strategies (i.e., phenotype-based status determination) could help to use CDA status as a biomarker for developing adaptive dosing strategies with nucleosidic analogs.
authors.affiliation: INSERM UMR_S911 Aix-Marseille University, SMARTc, CRO2, Pharmacokinetics Unit , UFR Pharmacie 27 Bd Jean Moulin 13385 Marseille , France joseph.ciccolini@univ-amu.fr.
authors.forename: Cindy
authors.initials: C
authors.lastname: Serdjebi
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
mesh_terms: D000328:Adult; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D002648:Child; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009705:Nucleosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic
chemical_list: D000964:Antimetabolites, Antineoplastic; D009705:Nucleosides; D003564:Cytidine Deaminase
keywords: adaptive dosing strategy; cytidine deaminase; nucleosidic analogs; pharmacogenetics