Induction of metallothionein-3 transcription as a pharmacodynamic biomarker for histone deacetylase inhibitor MGCD0103 in vitro and in vivo Free

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Histone deacetylases (HDACs) are important enzymes in the regulation of gene expression by deacetylation of histones and other cellular proteins. We have developed a novel isotype-selective HDAC inhibitor, MGCD0103, for human cancer therapy. Traditionally, pharmacodynamic (PD) effects of other HDAC inhibitors under clinical investigations were mainly monitored by analysis of histone acetylation or HDAC enzyme activity in peripheral white cells. Since HDAC inhibitors are transcriptional regulators and their biological effects are not exclusively dependent on histone acetylation, we sought to develop a more quantitative and biologically relevant PD marker for MGCD0103 in clinical trials for solid tumors. From expression analysis, we observe that transcription of metallothionein-3 (MT3), a metal binding protein with a wide range of physiological activity in cells, was induced by MGCD0103 both in a dose-dependent and time-dependent manner. Class I HDAC inhibition is required for the induction of MT3 transcription in human cancer cells in vitro. In implanted tumors from mice treated with MGCD0103 in vivo, induction of MT3 correlates with induction of p21 and histone acetylation. Consistent with the induction of MT3 expression in human cancer cells in vitro and in vivo, induction of MT3 transcription is also induced by MGCD0103 in a dose-dependent manner ex vivo in peripheral white cells from healthy volunteers and patients with solid tumors. We conclude that transcription of MT3 could be used as a PD marker for MGCD0103 in solid tumor trials and the biological significance of the induction of MT3 expression in tumors and peripheral white cells will be discussed.