Recent evidence demonstrates that epigenetic silencing of genes is associated 
with myelodysplasia and that a worse prognosis may be correlated with 
hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor 
p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at 
low doses, acts as a hypomethylating agent and is fivefold to tenfold more 
active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved 
drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have 
demonstrated that decitabine has activity in patients with MDS. Preliminary 
results of a phase III multicenter North American trial comparing low-dose 
decitabine to supportive care verified that therapy with decitabine resulted in 
higher response rates, improved quality of life, and prolonged time to leukemic 
transformation and/or death. However, further elucidation of its mechanism of 
action is required, as clinical response to decitabine does not correlate with 
demethylation of the p15 gene promoter or the repetitive DNA element LINE. 
Decitabine appears to upregulate both hypermethylated and nonmethylated genes. 
Ongoing studies aim to determine the optimal dose, schedule, and route of 
administration of decitabine, and to evaluate whether efficacy can be improved 
by using it in combination with other agents, such as histone deacetylase 
inhibitors.