Histone Deacetylase Inhibitors

Chromatin remodeling is part of the epigenetic changes seen during neoplastic transformation. While promoter hypermethylation is associated with silencing of tumor suppressor genes, it is not the only modification that controls chromatin condensation and promoter activity. Posttranslational modifications, such as acetyla-tion, methylation, and phosphorylation of histone proteins comprising the chromatin nucleosomes, are responsible for formation of complexes that control gene expression. Typically, acetylation of the lysine residues in the histone "tail" by acetyltransferases (HAT) leads to "open" transcriptionally active chromatin, whereas deacetylation, dependent on histone deacetylases (HDAC), leads to "closed" inactive chromatin. HDAC activity is associated with promoter methylation, and it is the combination of both that contributes to promoter inactivation.10 As therapeutic reactivation of tumor suppressor genes has gained the attention of drug companies, multiple HDAC inhibitors have been investigated. Since HDAC inhibitors are often cell-cycle and tissue specific, these agents have been found to exert pleiotropic effects.

Butyrate is an acetylating agent that has been used to induce expression of fetal hemoglobin in sickle cell anemia and thalassemia, but proved unsuccessful for the treatment of AML in phase II trials.11 Sodium phenylbu-tyrate (PB), a derivative thought to be deliverable in oral form, has been shown to induce histone acetylation, p21 expression, G1 cell-cycle arrest, and apoptosis in vitro.12 In a trial conducted by Gore et al.,13 PB was given for 7/28 or 21/28 days to MDS and AML patients, with improvement in thrombocytopenia and neutrope-nia seen in a small number of patients. A dose-limiting toxicity of reversible encephalopathy was due to accumulation of phenylacetate. Currently, oral forms of PB are being investigated. Valproic acid, an oral antiepilep-tic agent, SAHA (suberoylanilide hydroxamic acid), and FK 228 (with FDA approval for cutaneous T-cell lymphoma) are newer HDAC inhibitors currently undergoing clinical trials.

As chromatin remodeling involves a balance between CpG methylation and histone modification, a phase I trial of sequential administration of Aza-C and PB was initiated in MDS. The dose de-escalation trial of varying doses of Aza-C followed by a 7-day continuous infusion of PB was well tolerated, with significant clinical responses.14 Additional studies combining DAC with valproic acid are underway, with monitoring of methylation, acetylation, and gene re-expression.

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