Histone deacetylase inhibitors in clinical development.

In addition to a variety of other novel agents, interest in histone deacetylase inhibitors (HDACIs) as antineoplastic drugs has recently accelerated and increasing numbers of these compounds have entered clinical trials in humans. HDACIs represent a prototype of molecularly targeted agents that perturb signal transduction, cell cycle-regulatory and survival-related pathways. Newer generation HDACIs have been introduced into the clinical arena that are considerably more potent on a molar basis than their predecessors and are beginning to show early evidence of activity, particularly in hematopoietic malignancies. In addition, there is an increasing appreciation of the fact that HDACIs may act through mechanisms other than induction of histone acetylation and, as in the case of other molecularly-targeted agents, it is conceivable that the ultimate role of HDACIs in cancer therapy will be as modulators of apoptosis induced by other cytotoxic agents. One particularly promising strategy involves attempts to combine HDACIs with other novel agents to promote tumour cell differentiation or apoptosis. The present review focuses on recent insights into the mechanisms by which HDACIs exert their anticancer effects, either alone or in combination with other compounds, as well as attempts to translate these findings into the clinic.