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Histone Deacetylase Inhibitor Pharmacodynamic Analysis by Multiparameter Flow Cytometry

Address correspondence to Jane B. Trepel, Medical Oncology Clinical Research Unit, CCR, NCI, NIH, Building 10, Rm 12N230, 10 Center Drive, Bethesda, MD 20892, USA; tel 301 496 1547; fax 301 402 0172; e-mail trepel{at}helix.nih.gov. The current address of E. A. Sausville M.D., Ph.D., is: Greenebaum Cancer Center, University of Maryland Medical Center, 22 S Greene Street, Baltimore, MD 21201, USA.

Histone deacetylase (HDAC) inhibitors are a promising new class of anticancer drug. The aim of this study was to develop a versatile and sensitive technique for the pharmacodynamic (PD) assessment of HDAC inhibitor activity as monotherapy and in combination therapy. A multiparameter flow cytometric assay was developed initially in healthy donor lymphocytes and leukemia cell lines, and then tested in peripheral blood of solid tumor patients and in bone marrow aspirates of leukemia patients on phase I trials of the HDAC inhibitor MS-275. A technique was developed that allows highly sensitive single parameter determination of HDAC inhibitor activity in as little as 50 µl of whole blood. Multiparameter analysis enabled correlation on a single cell basis of protein acetylation with biologically relevant markers including cell lineage antigens, an apoptosis marker, and PD markers of other anti-cancer agents. The level of protein acetylation can be readily detected and quantified in peripheral blood or in bone marrow aspirates by flow cytometric analysis. The technique described has significant advantages for the PD assessment of HDAC inhibitors as monotherapy and as a component of combination therapy trials.

Keywords: HDAC, pharmacodynamic analysis, multiparameter, flow cytometry

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