Histone Deacetylase Inhibitors

Histone deacetylase inhibitors are a new class of chemotherapeutic agents that induce growth arrest and apoptosis of neoplastic cells by binding to HDACs and modulating gene expression.

Depsipeptide, FR901228, is an HDAC inhibitor that has demonstrated potent in vitro and in vivo cytotoxic activity against murine and human tumor cell lines. In a phase I trial of depsipeptide conducted at the National Cancer Institute, three patients with CTCL had a partial response, and one patient with peripheral T-cell lymphoma, unspecified, had a complete response.76 Another HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), has also demonstrated activity in patients with T-cell lymphoma. When administered intravenously in patients with advanced cancer, the maximal-tolerated dose of SAHA was 300 mg/ m2/day X 5 days for 3 weeks. An accumulation of acetylated histones in peripheral blood mononuclear cells and biopsied tumor tissue was demonstrated up to 4 h postinfusion. SAHA demonstrated clinical activity in patients with CTCL, and phase II clinical trials are being pursued. The activity of the HDAC inhibitors in B-cell NHL is currently under investigation.

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