Decitabine.
OBJECTIVE
Decitabine is a cytosine analogue synthesized in the 1960s that is currently enjoying a revival of interest prompted by the elucidation of DNA methylation inhibition as its major mechanism of action, along with increased understanding of the role of DNA methylation in epigenetic dysregulation in cancer. These advances have turned this agent from just another cytosine analogue into a targeted drug aimed at reversing epigenetic silencing in cancer cells. Here, recent clinical and translational studies with decitabine are reviewed.


RESULTS
Scientists are now taking a closer look at this drug as a targeted agent, with particular attention to schedules of administration and mechanisms of in vivo efficacy. Two phase II trials have reported substantial clinical activity of decitabine in the myelodysplastic syndrome and in chronic myelogenous leukemia. There is considerable interest in combining decitabine with histone deacetylase inhibitors and in using it to sensitize cells to chemotherapy or to biologic therapy. Finally, ongoing efforts are deciphering the in vivo mechanisms of responses seen after decitabine administration.


CONCLUSIONS
Decitabine, an old drug, has now made a comeback as a targeted agent and a prototype for epigenetic therapy in cancer. Doses, schedules of administration, and the development of rational combinations including this agent must all take this critical mechanism of action into account.
Issa
Jean-Pierre
JP
Department of Leukemia, M. D. Anderson Cancer Center, Houston, TX 77030, USA. jpissa@mdanderson.org
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine