Role of cytidine deaminase in toxicity and efficacy of nucleosidic analogs

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Keywords:

• adaptive dosing strategy
• cytidine deaminase
• nucleosidic analogs
• pharmacogenetics

Declaration of interest

C Serdjebi has received a grant from Fondation pour la Recherche Medicale FM20140629931. J Ciccolini has a patent US20130011392A1 on measurement of CDA activity. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript other than those disclosed.

Notes

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