title: Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101.
abstract: 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 IC(50) of 27 nM and induces a concentration-dependent (0.2-5 micro M) increase in acetylation of histone H4 in tumor cell lines. PXD101 is cytotoxic in vitro in a number of tumor cell lines with IC(50)s in the range 0.2-3.4 micro M 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.
authors.affiliation: Department of Medical Oncology, University of Glasgow, Cancer Research United Kingdom Beatson Laboratories, Glasgow, G61 1BD, United Kingdom. Jane.Plumb@beatson.gla.ac.uk
authors.forename: Jane A
authors.initials: JA
authors.lastname: Plumb
authors.forename: Paul W
authors.initials: PW
authors.lastname: Finn
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Williams
authors.forename: Morwenna J
authors.initials: MJ
authors.lastname: Bandara
authors.forename: M Rosario
authors.initials: MR
authors.lastname: Romero
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Watkins
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: La Thangue
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013449:Sulfonamides; D006655:Histone Deacetylases; C487081:belinostat