5-Azacytidine (5AC), a hypomethylating agent, is clinically used for the treatment of patients with
myelodysplastic syndromes (MDS).
Cytidine deaminase (CDA) is a key
enzyme in the detoxification of 5AC. We investigated whether the CDA expression could predict response to 5AC in MDS. Among
leukemia-derived cell lines, MDS-L, an MDS-derived cell line with a relatively low CDA expression level, was found to be the most sensitive to 5AC. Combination with
tetrahydrouridine, an inhibitor of CDA, synergistically potentiated the cytotoxic effect of 5AC. Treatment with 5AC markedly enhanced the expression level of CDA
mRNA and showed demethylation at CpG sites in the 5'-flanking region of the CDA gene. We further compared the
protein expression levels of CDA in matched clinical samples before and
after treatment with 5AC in bone marrow cells from 8 MDS patients by an immunohistochemical analysis. The CDA expression level showed an approximately 2- to 3-fold increase after 5AC treatment in 3 of these cases, and these three patients with relatively higher CDA expression levels after 5AC treatment all showed better clinical responses to 5AC. In contrast, the 5 remaining patients, whose CDA expression showed no augmentation, observed no clinical benefit. Taken together, the optimized determination of the CDA expression levels before and after 5AC treatment, and the methylation status at CpG sites of 5'-flanking region of the CDA gene, may contribute to the development of precise 5AC
therapy for MDS.