Decitabine Dosing Schedules

5-Aza-2′-deoxycytidine (decitabine; Dacogen™, MGI Pharma, Inc, Bloomington, MN) is a cytidine analog that inhibits DNA methyltransferases resulting in loss of DNA methylation with subsequent gene re-expression. This compound was first synthesized over 40 years ago and since that time much information has been learned regarding its mechanism of action. It took nearly 20 years before the dual mechanism of action was elucidated. At high doses decitabine is cytotoxic, while lower doses are associated with demethylating activity. This information sparked further clinical trials using a lower dosing schedule since the original studies using higher doses were associated with significant myelosuppression and induction toxicity. Current trials using lower dosing schedules, particularly in patients with hematologic malignancies, have shown significant promise for the future use of demethylating agents. Sequential and/or randomized phase I/II studies have suggested that decitabine is most active when administered at relatively low doses given via a short infusion. The drug is less active and more toxic when administered via continuous infusion, and increasing dose-intensity resulted in a higher response rate, suggesting a relationship between peak drug levels and response. Even with all the information we have learned, there is still a need to determine the optimal dosing schedule and the development of alternative dosing forms.