Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used
decitabine as a classical anticancer
drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m(2) per course. At these doses,
decitabine was found to be active in
leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in
cancer and the role of
decitabine in epigenetic (hypomethylating)
therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at 'optimal
biologic' doses that modulate hypomethylation). In these dose schedules of
decitabine (100 to 150 mg/m(2) per course), the
drug was found to be active with manageable side effects in patients with
myelodysplastic syndromes (MDS) and other myeloid
tumors. Optimizing dosing schedules of
decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that
decitabine is an active
therapy that alters the natural course of MDS. Combination
therapies that augment the epigenetic effect of
decitabine will likely improve responses and extend its use for the treatment of other
malignancies.