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Department of Medical Oncology, University of Glasgow, Cancer Research United Kingdom Beatson Laboratories, Glasgow, G61 1BD [J. A. P., R. B.], and TopoTarget Prolifix, Abingdon, OX14 4RY [P. W. F., R. J. W., M. J. B., M. R. R., C. J. W., N. B. L.], United Kingdom

¹ To whom requests for reprints should be addressed, at Department of Medical Oncology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Bearsden, Glasgow G61 1BD, United Kingdom. E-mail: Jane.Plumb{at}beatson.gla.ac.uk

Histone acetylation has a central role in the control of gene expression, influencing transcriptional control of many genes, including tumor suppressor genes. PXD101 is a novel hydroxamate-type inhibitor of histone deacetylase activity that inhibits histone deacetylase activity in HeLa cell extracts with an IC₅₀ of 27 nM and induces a concentration-dependent (0.2–5 µM) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC₅₀s in the range 0.2–3.4 µM as determined by a clonogenic assay and induces apoptosis. Treatment of nude mice bearing human ovarian and colon tumor xenografts with PXD101 (10–40 mg/kg/day i.p.) daily for 7 days causes a significant dose-dependent growth delay with no obvious signs of toxicity to the mice. Growth delay is also observed for xenografts of cisplatin-resistant ovarian tumor cells. A marked increase in acetylation of H4 is detected in blood and tumor of mice 3 h after treatment with PXD101. The inhibition of growth of human tumor xenografts in mice, with no apparent toxicity, suggests that PXD101 has potential as a novel antitumor agent. Furthermore, the ability to measure histone acetylation in blood samples could provide a suitable pharmacodynamic end point to monitor drug activity.