Histone deacetylase inhibitors: Development as cancer therapy Journal Article


Authors: Marks, P. A.; Richon, V. M.; Kelly, W. K.; Chiao, J. H.; Miller, T.; Bock, G.; Goode, J.
Article Title: Histone deacetylase inhibitors: Development as cancer therapy
Title Series: Novartis Foundation Symposia
Abstract: Histone deacetylase (HDAC) inhibitors represent a new class of targeted anticancer agents. A number of structural classes of HDAC inhibitors have been developed of which several are in clinical trials, including phenylbutyrate (PB) and related compounds; the hydroxamic acids, suberoylanilide hydroxamic acid (SAHA) and depsipeptide (FK-228); and the benzamides, MS-275 and C1-994. This review will focus on our studies with the hydroxamic acid HDAC inhibitors, of which SAHA is the lead agent. X-ray crystallographic studies with a HDAC homologue (HDLP) demonstrated that the hydroxamic acid group, most of the aliphatic chain and part of the phenyl amino group of SAHA inserts into the pocket-like catalytic site of the enzyme, at the base of which is a zinc molecule. SAHA inhibits the activity of class I and II HDACs and is selective in altering gene expression. SAHA is synergistic in its anticancer activity with radiation, kinase inhibitors, cytotoxic agents and differentiating agents. In phase I clinical trial with orally administered SAHA the agent caused accumulation of acetylated histones in peripheral mononuclear cells and tumour cells, has excellent bioavailability and has shown antitumour activity in patients with haematologic and solid tumours.
Keywords: laryngeal neoplasms; neoplasm; neoplasms; metastasis; classification; lung neoplasms; pathology; lung tumor; drug antagonism; lung; histone deacetylases; histone deacetylase; larynx tumor; humans; human; article
Journal Title: Novartis Foundation Symposia
Volume: 259
ISSN: 1935-4657
Publisher: Wiley Periodicals, Inc  
Publication Place: Chichester, UK
Date Published: 2004-01-01
Start Page: 269
End Page: 284
Language: English
PROVIDER: scopus
PUBMED: 15171260
DOI: 10.1002/0470862637.ch20
DOI/URL:
Notes: Chapter in "Reversible Protein Acetylation" (ISBN: 9780470862612) -- Novartia Found. Symp. -- Cited By (since 1996):58 -- Export Date: 16 June 2014 -- Source: Scopus
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MSK Authors
  1. William K Kelly
    112 Kelly
  2. Paul Marks
    143 Marks