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.