Pharmacodynamic responses to DNA methyltransferase inhibition

The DNA methyltransferase inhibitors, 5-azacytidine and decitabine, were initially developed at high dose for clinical use as classical cytotoxic agents and only later reidentified as epigenetically active drugs capable of reexpressing genes silenced by DNA methylation. Their clinical activity in myeloid malignancy has resulted in rapid acceptance into clinical practice for the treatment of patients with MDS and AML, a group of patients for whom other treatment strategies have been largely ineffective. Despite widespread clinical use in these patients, the mechanisms responsible for their efficacy remain opaque, and controversy remains regarding the relative contributions of demethylation of silenced tumor suppressor genes with induction of apoptosis and differentiation, induction of CG antigens expression with resultant antitumor immunity, and DNA damage events.