Histone deacetylase inhibitors in cancer therapy.
Histones are a family of nuclear proteins that interact with DNA, resulting in DNA being wrapped around a core of histone octamer within the nucleosome. Acetylation/deacetylation of histones is an important mechanism that regulates gene expression and chromatin remodeling. Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic drugs that regulate gene expression by enhancing the acetylation of histones, and thus inducing chromatin relaxation and altering gene expression. HDAC inhibitors have been shown in preclinical studies to have potent anticancer activities. A range of structurally diverse HDAC inhibitors have been purified as natural products or synthetically produced. Due to the promising preclinical activity of these agents, numerous clinical trials have been initiated. In this review, the results of published data of single agent and combination trials of these drugs are reviewed, with a focus on dosing, scheduling and toxicity. Although still early in drug development, there is a picture that is starting to develop as to the common toxicities and which tumors seem to be the most susceptible to this class of drugs.
Rasheed
Walid K
WK
Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, Victoria 8006, Australia.
Johnstone
Ricky W
RW
Prince
H Miles
HM
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006655:Histone Deacetylases