Optimizing therapy with methylation inhibitors in myelodysplastic syndromes: dose, duration, and patient selection.
Azacitidine (Vidaza, Pharmion Corp., Boulder, CO, USA) and decitabine (Dacogentrade mark, SuperGen, Inc., Dublin, CA, USA, and MGI Pharma, Inc., Bloomington, MN, USA) are DNA methyltransferase (DNMT) inhibitors that have clinical activity in patients with myelodysplastic syndromes. Mechanism-based laboratory studies suggest that clinical optimization of therapy with DNMT inhibitors needs to include optimizing intracellular drug uptake and maximizing drug exposure over time while still using lower doses to avoid cytotoxicity. Clinical studies suggest that increased dose intensity and multiple cycles of administration substantially increase response rates. Other strategies for optimizing the efficacy of DNMT inhibitor therapy also include identification of patients that are best qualified for treatment, and defining in vivo mechanisms of patient responses. In the future, combination strategies to increase gene reactivation and to take advantage of increased expression of target genes may be critical for achieving optimal results.
Issa
Jean-Pierre
JP
Section of Translational Research, Department of Leukemia at the MD Anderson Cancer Center, University of Texas, Houston 77030, USA. jpissa@mdanderson.org
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004334:Drug Administration Schedule; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D018579:Patient Selection; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine