In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies.
Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.
Hackanson
Björn
B
Department of Hematology/Oncology, University of Freiburg Medical Center, Freiburg, Germany.
Robbel
Christian
C
Wijermans
Pierre
P
Lübbert
Michael
M
D000208:Acute Disease; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002869:Chromosome Aberrations / Q000187:drug effects; D002986:Clinical Trials as Topic; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D050762:Cyclin-Dependent Kinase Inhibitor p15; D000077209:Decitabine; D001374:Azacitidine