Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms.
Optimal reexpression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of aza-CR. Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders. Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation. Gene demethylation correlated with the area under the aza-CR plasma concentration-time curve. Administration of both drugs was associated with induction of acetylation of histones H3 and H4. This study provides the first demonstration that molecular mechanisms responsible for responses to DNA methyltransferase/histone deacetylase inhibitor combinations may include reversal of aberrant epigenetic gene silencing. The promising percentage of major hematologic responses justifies the testing of such combinations in prospective randomized trials.
Gore
Steven D
SD
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21287, USA. gorest@jhmi.edu
Baylin
Stephen
S
Sugar
Elizabeth
E
Carraway
Hetty
H
Miller
Carole B
CB
Carducci
Michael
M
Grever
Michael
M
Galm
Oliver
O
Dauses
Tianna
T
Karp
Judith E
JE
Rudek
Michelle A
MA
Zhao
Ming
M
Smith
B Douglas
BD
Manning
Jasper
J
Jiemjit
Anchalee
A
Dover
George
G
Mays
Abbie
A
Zwiebel
James
J
Murgo
Anthony
A
Weng
Li-Jun
LJ
Herman
James G
JG
D000107:Acetylation / Q000187:drug effects; D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010654:Phenylbutyrates; D004248:DNA (Cytosine-5-)-Methyltransferases; D006655:Histone Deacetylases; D001374:Azacitidine