Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101.
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.
Plumb
Jane A
JA
Department of Medical Oncology, University of Glasgow, Cancer Research United Kingdom Beatson Laboratories, Glasgow, G61 1BD, United Kingdom. Jane.Plumb@beatson.gla.ac.uk
Finn
Paul W
PW
Williams
Robert J
RJ
Bandara
Morwenna J
MJ
Romero
M Rosario
MR
Watkins
Claire J
CJ
La Thangue
Nicholas B
NB
Brown
Robert
R
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
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013449:Sulfonamides; D006655:Histone Deacetylases; C487081:belinostat