Gender effects on cytidine analogue metabolism and myelodysplastic syndrome treatment outcomes

Abstract

In vivo, half-lives of cytidine analogues such as 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), are determined largely by cytidine deaminase (CDA), an enzyme that rapidly metabolizes these drugs into inactive uridine counterparts. Genetic factors influence CDA activity, and hence, could impact 5-azacytidine/decitabine levels and efficacy, a possibility requiring evaluation. Using an HPLC assay, plasma CDA activity was confirmed to be decreased in individuals with the CDA SNP A79C. More interestingly, there was an even larger decrease in females. Explaining the decrease in enzyme activity, 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 effect of shortening half-life of S-phase specific therapy was amplified in low S-phase fraction disease (e.g., MDS). Accordingly, in multivariate analysis of MDS patients treated with 5-azacytidine/decitabine, overall survival was significantly worse in males.