Azacitidine: activity and efficacy as an epigenetic treatment of myelodysplastic syndromes.

5´-azacitidine is a ring analog of cytosine, differing from the natural nucleoside because it has a nitrogen in lieu of carbon in position five of the pyrimidine. Despite being synthesized approximately 40 years ago it has only recently been employed with success at low doses in the treatment of myelodysplastic syndromes (MDS). This drug has hypomethylating activity and, possibly, exerts its action by reinducing expression of genes silenced by the hypermethylation of CpG islands in their promoters. Azacitidine is administered prevalently subcutaneously (75 mg/m(2)/day for 7 days every 28 days) as the pharmacokinetics and pharmacoavailability are almost equivalent to the intravenous route. It was the first agent demonstrated to delay acute myeloblastic leukemia transformation and to prolong survival for patients with higher risk MDS, and it was approved in 2004 by the US FDA for treatment of all MDS risk categories. Azacitidine allows transfusion independence in more than 40% of treated MDS patients, and has opened a new era in the treatment of MDS and the use of 'epigenetic drugs'. To correctly use this agent and obtain hematological improvements that lead to a prolonged overall survival of MDS patients, hematologists have to modify their perspective and their usual expectations from a chemotherapy-like regimen. Azacitidine may also be administered quite safely to elderly patients presenting comorbidities and it is well tolerated in an out-patient regimen. Its mode of action does not necessarily require cytotoxicity and does not induce a rapid response. Several rounds of therapy and of consequent hypomethylation of target genes are necessary to re-express silenced genes critical to differentiation and the majority of patients will respond after three to six cycles of therapy.