Combined DNA Methyltransferase and Histone Deacetylase Inhibition in the Treatment of Myeloid Neoplasms

摘要: Optimal reexpression of most genes silenced through promoter methylation requires the sequential application DNA methyltransferase inhibitors followed by histone deacetylase in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated inhibitor 5-azacitidine (aza-CR) sodium phenylbutyrate. Major responses associated cytogenetic complete response developed patients receiving prolonged dosing schedules aza-CR. Bisulfite sequencing p15 marrow during first cycle treatment showed heterogeneous allelic demethylation three responding patients, suggesting ongoing within clone, but no two nonresponders. Six six pretreatment CDH-1 promoters reversed therapy (methylation-specific PCR), whereas none nonresponders any demethylation. Gene correlated area under aza-CR plasma concentration-time curve. Administration both drugs was induction acetylation histones H3 and H4. This study provides demonstration that molecular mechanisms responsible for to methyltransferase/histone combinations may include reversal aberrant epigenetic gene silencing. The promising percentage major hematologic justifies testing such prospective randomized trials.