Can cytidine deaminase be used as predictive biomarker for gemcitabine toxicity and response?

Cytidine deaminase (CDA) plays an important role in the degradation of cytidine analogues, such as gemcitabine, cytarabine (ara‐C), azacytidine, and aza‐2′‐deoxycytidine, which are widely used for the treatment of several solid and haematological malignancies. Moreover, it activates capecitabine metabolism resulting in 5‐fluorouracil (5FU). CDA plays an important role in the pharmacokinetics of these analogues; Yonemori et al demonstrated that a deficiency of CDA due to a specific polymorphisms would lead to excessive toxicity, while Bengala et al demonstrated that both a high expression and activity of CDA in blood cells were associated with an increased degradation of gemcitabine and a lower response rate in patients with pancreatic cancer. Briefly, a lower CDA activity will lead to a decreased gemcitabine deamination to 2′, 2′‐difluoro‐2′‐deoxyuridine (dFdU), resulting in increased plasma gemcitabine concentrations in these patients. Thus, systemic CDA is critical for the therapeutic efficacy of gemcitabine. CDA was determined by evaluation of its gene expression and activity in white blood cells, but also by genetic polymorphisms. Certain polymorphisms (such as CDA Lys27Gln) are associated with a decreased red blood cell CDA activity, but there was a large overlap in enzyme activities. In their paper, Cohen et al showed that the c.‐33_‐31delC SNP contributed only 4.1% to the variation in CDA activity. Although significant, this does not seem relevant considering the much larger contribution of, eg, neutrophil count (24.8%). These data raised the question which assay should be used to determine CDA in patients: a genotypic assay such as SNPs or gene expression, or a phenotypic assay such as an activity assay in a blood compartment. Since cytidine analogues are widely used, a simple test would be preferred. Moreover, inflammation results in a large variation of CDA activity, leading to the hypothesis that CDA may be a marker of rheumatoid arthritis. Because the variation induced by inflammation may be larger than that caused by a genotype, a phenotypic assay measuring enzyme activity to evaluate fluctuations in CDA activity would be preferable over a genomic assay. Cohen et al described an independent cross‐validation of a phenotypic assay, earlier developed by Ciccolini et al. CDA activity can be measured using several methods. The natural substrates for CDA are cytidine and deoxycytidine, while many cytidine analogues are excellent substrates as well, although they show different enzyme kinetics. Classical assays used a radioactive substrate, which in