Pharmacodynamic effect of MGCD0103, an oral isotype-selective histone deacetylase (HDAC) inhibitor, on HDAC enzyme inhibition and histone acetylation induction in phase I clinical trials in patients (pts) with advanced solid tumors or non-Hodgkin’s lymphoma (NHL)

Abstract

9631 Background: Histone deacetylase inhibitors represent a new class of targeted anticancer agents. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Thus, inhibition of these enzymes might restore normal growth control. Several HDAC inhibitors, including MGCD0103, are in clinical trials. Methods: To analyze the pharmacodynamic properties of MGCD0103 in Phase I clinical studies, we have used a variety of biological assays to monitor HDAC inhibitory activity. An HDAC enzyme assay using intact white cells from patients was used to monitor the enzyme inhibitory activity of MGCD0103, while histone acetylation in these cells was analyzed by Western blotting, fluorescence-activated cell sorting (FACS) and enzyme-linked immunosorbent assay (ELISA). Results: We demonstrate that, in 3 of the first 7 patients for whom comparative data are available, HDAC enzyme inhibition correlates positively with histone acetylation induction in their peri...