ABSTRACT
Introduction ............................................................................................................ 368 Histone Acetyltransferases ..................................................................................... 368 Histone Deacetylases ............................................................................................. 368 HATs and HDACs in Cancer ................................................................................. 369 HDAC Inhibitors .................................................................................................... 371
Mechanism of Action ........................................................................................ 373 Effects on Gene Expression ......................................................................... 373 Effects on Cell Cycle .................................................................................... 374 Release of Reactive Oxygen Species ........................................................... 374 Nonhistone Protein Acetylation ................................................................... 374 Inhibition of DNA Repair ............................................................................. 375 Apoptosis Induction ..................................................................................... 375
Final Comments on Mechanism of Action........................................................ 375 HDIs in Clinical Trials ........................................................................................... 376
Single Agent Studies ......................................................................................... 376 Pharmacodynamics ........................................................................................... 377 Toxicity.............................................................................................................. 378 HDIs in Combination Therapy Trials ................................................................ 379
Histone deacetylase inhibitors (HDIs) belong to the broader category of epigenetic agents, which also include the DNA methyltransferase inhibitors (5-azacytidine and decitabine), and several other agents in clinical development. Vorinostat and romidepsin were the first HDIs to be approved for the treatment of cancer and were approved based on their activity in T-cell lymphomas. Although these agents cause rapid and durable disease response in T-cell lymphoma, the mechanism underlying this is not entirely clear, as the agents induce an array of biological effects. Some of these have been studied for potential roles in combination therapies.
