Assays for pharmacodynamic analysis of histone deacetylase inhibitors.
Histone deacetylase inhibitors (HDACIs) are a promising new class of targeted anticancer drugs. The pharmacodynamic (PD) assessment of whether a drug has hit its target is critically important to the successful development of any molecular targeted therapy. In the case of HDACIs there are many issues to be considered in PD development and implementation. Although originally it was thought that measurement of core histone hyperacetylation in peripheral blood mononuclear cells might suffice as a PD marker, as the field is evolving it is becoming evident that other measures may be essential, and are likely to be tumour context specific. This paper provides an overview of the assays that have been performed thus far in HDACI clinical trials, with an analysis of relative strengths and weaknesses, and a delineation of the complexity of HDACI PD analysis. Consideration is given to where new approaches are needed and potential approaches for future monotherapy and combination therapy trials are suggested.
Chung
Eun Joo
EJ
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Medical Oncology Branch, Building 10, Room 12N230, 10 Center Drive, Bethesda, MD 20892, USA.
Lee
Min-Jung
MJ
Lee
Sunmin
S
Trepel
Jane B
JB
D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases