Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay.

Abstract

PURPOSE:

The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay.

EXPERIMENTAL DESIGN:

Boc-Lys(epsilon-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheral WBC ex vivo, in mice in vivo, and in human patients.

RESULTS:

MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheral WBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheral WBC correlated with induction of histone acetylation in blood and in implanted tumors in mice. In cancer patients, sustained pharmacodynamic effect of MGCD0103 was visualized only by dose-dependent enzyme inhibition in peripheral WBC but not by histone acetylation analysis.

CONCLUSIONS:

This study shows that MGCD0103 has sustained pharmacodynamic effects that can be monitored both in vitro and in vivo with a cell-based HDAC enzyme assay.

• Authors: Claire Bonfils, Ann Kalita, Marja Dubay, Lillian L Siu, Michael A Carducci, Gregory Reid, Robert E Martell, Jeffrey M Besterman, Zuomei Li
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 11 Pg. 3441-9 (Jun 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18519775 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Pyrimidines
• mocetinostat
• Histone Deacetylases

Topics

• Animals
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzamides (administration & dosage, adverse effects, pharmacokinetics)
• Biological Assay (methods)
• Cell Line, Tumor
• Drug Administration Schedule
• Enzyme Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Histone Deacetylase Inhibitors
• Histone Deacetylases (analysis, drug effects)
• Humans
• Inhibitory Concentration 50
• Mice
• Neoplasms (drug therapy)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Xenograft Model Antitumor Assays