The augmented expression of the cytidine deaminase gene by 5-azacytidine predicts therapeutic efficacy in myelodysplastic syndromes
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Yuichi Murakami1,2,*, Yoshizo Kimura3,*, Akihiko Kawahara4,*, Shohei Mitsuyasu5, Hidetoshi Miyake5, Kaoru Tohyama6, Yoshio Endo7, Nao Yoshida8, Yutaka Imamura8, Kosuke Watari2, Mayumi Ono2, Takashi Okamura9 and Michihiko Kuwano1
1 Cancer Translational Research Center, St. Mary's Institute of Health Sciences, Kurume, Japan
2 Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
3 Department of Pathology, St. Mary’s Hospital, Kurume, Japan
4 Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan
5 Department of Pharmacy, St. Mary's Hospital, Kurume, Japan
6 Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan
7 Central Research Resource Branch, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
8 Department of Hematology, St. Mary's Hospital, Kurume, Japan
9 Hematology and Oncology Center, St. Mary’s Hospital, Kurume, Japan
* These authors contributed equally to this work
Keywords: myelodysplastic syndromes; cytidine deaminase; 5-azacytidine; DNA methylation; hypomethylating agent
Received: December 13, 2018 Accepted: March 04, 2019 Published: March 19, 2019
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.
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