Azacytidine: first therapeutic opportunity for myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are clonal disorders characterized by ineffective hematopoiesis, wich can lead either to fatal cytopenia or acute myelogenous leukemia (AML). During the last 14 years, important progress has been made in the understanding of the biology and prognosis of MDS; risk-adapted treatment strategies were estabilished, according to the median age (60-75 years ) of MDS patients and the individual history of the desease (number of cytopenias, cytogenetic changes, transfusion requirements). The use of allogeneic bone marrow transplantation for MDS patients currently offers the only potentially curative treatment, but this kind of therapy is not available for the typical MDS patient, who is > 60 years of age. The development of new molecules directed against specific molecular targets, with few adverse effects, is the hope for the future. DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. 5-Azacytidine, a ring analog of the naturally occurring pyrimidine nucleoside cytidine, showed some interesting and promising effects on cell differentiation, gene expression, and DNA synthesis and metabolism. Since the early 1970s, Azacytidine at higher doses has been investigated for the treatment of acute leukemia. Azacytidine is thought to have two main mechanisms of antineoplastic action: ‐a) cytotoxicity, resulting from incorporation into RNA and DNA; -b) hypomethylation, restoring normal growth control and differentiation in hematopoietic cells. Induction of DNA hypomethylation