Targeting epigenetic abnormalities with histone deacetylase inhibitors.
BACKGROUND
Alterations in chromosome structure play critical roles in the control of gene transcription. These "epigenetic" alterations include modification of histones and other proteins by acetylation and/or phosphorylation. Normally, these modifications are balanced finely and are highly reversible in normal tissues, but they may be imbalanced and heritable in tumor cells. Histone deacetylase inhibitors increase histone acetylation, thereby modulating the expression of a subset of genes in a coordinated fashion. Several tumor suppressor genes associated with the malignant phenotype are repressed by epigenetic mechanisms in sporadic cancers. Thus, therapy with histone deacetylase inhibitors may alter tumor phenotype to inhibit growth in such tumors.


METHODS
The authors reviewed the rationale for histone deacetylase inhibitors as potential anticancer agents and reviewed some preclinical and early clinical trial data with various classes of histone deacetylase inhibitors.


RESULTS
Preclinical and clinical antitumor activity has been observed. Toxicities include fatigue, myelosuppression, and cardiac abnormalities.


CONCLUSIONS
Histone deacetylase inhibitors have shown promising activity in some solid tumors and hematologic malignancies.
Conley
Barbara A
BA
Division of Hematology/Oncology, Department of Medicine, College of Human Medicine, B414 Clinical Center, Michigan State University, East Lansing, Michigan 48824, USA. barbara.conley@hc.msu.edu
Wright
John J
JJ
Kummar
Shivaani
S
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004794:Enzyme Repression / Q000187:drug effects; D044127:Epigenesis, Genetic; D005544:Forecasting; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors