DNA methyltransferase inhibitors in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) resulting from a clonal stem cell is a heterogeneous disease that complicates therapeutic decisions. Most patients are of advanced age with attendant comorbities, making treatment choices difficult. Current treatment options include bone marrow transplant, which appears to be the only curative option, and supportive care. In elderly patients, risks for transplant are high and supportive-care treatments are ineffective. However, considerable progress has been made in understanding the pathology of MDS, which results from a series of progressive chromosomal assaults that lead to a release of various cytokines, loss of tumor suppressor genes, and changes in signal transduction pathways and in immune pathways. The neoplastic clone does not appear to mature; it stays in a fixed state of differentiation beyond which these cells do not progress. Hypermethylation of specific DNA sequences, which results in silencing transcription of proteins involved, has been implicated in this lack of differentiation. New clinical discoveries include the potential to block methylation, release transcriptional inactivation, and stimulate the normal myeloid cells to resume growth and differentiation. Therapies aimed at these new findings hold promise for safer treatment protocols and improved outcomes. One of these agents, azacitidine, is a nucleoside analog that has shown promising efficacy in high-risk MDS patients. Phase III studies have shown significant improvement in survival and quality of life with minimal side effects. Prolonged administration of azacitidine results in reactivation of normal hematopoiesis by its effect on inhibiting DNA methylation.