Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies.
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.
Jabbour
Elias
E
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. ejabbour@mdanderson.org
Issa
Jean-Pierre
JP
Garcia-Manero
Guillermo
G
Kantarjian
Hagop
H
D000964:Antimetabolites, Antineoplastic / Q000266:history / Q000493:pharmacokinetics / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000266:history / Q000493:pharmacokinetics / Q000494:pharmacology; D002986:Clinical Trials as Topic; D000077209:Decitabine; D004353:Drug Evaluation, Preclinical; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000188:drug therapy
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine