Monitoring the effect of belinostat in solid tumors by H4 acetylation.
Histone deacetylase (HDAC) inhibition is a novel entity in medical oncology, and several HDAC inhibitors are in clinical trials. One of them is the hydroxamic acid belinostat (PXD101) that has demonstrated therapeutic efficacy for several clinical indications. Acetylation of histones is a key event after treatment with HDAC inhibitors, and could thus be used as a marker for monitoring cellular response to HDAC inhibitor treatment. Here we describe the utility of a newly described monoclonal antibody against acetylated H4 for immunohistochemistry on paraffin-embedded fine needle biopsies from nude mice carrying A2780 human ovarian cancer xenografts. Acetylated H4 was monitored in vivo by immunohistochemistry during treatment with belinostat, and compared with pharmacokinetics in plasma and tumor tissue. We found an increased level of acetylated H4 15 min after a single treatment (200 mg/kg i.v.) with maximum level reached after 1 h. H4 acetylation intensity reflected the belinostat concentration in plasma and tumor tissue. The threshold level for belinostat activity, indicated by acetylated H4, correlated with belinostat plasma concentrations above 1,000 ng/ml. In conclusion, examination of H4 acetylation in fine needle biopsies using the T25 antibody may prove useful in monitoring HDAC inhibitor efficacy in clinical trials involving humans with solid tumors.
Marquard
Lena
L
Experimental Pathology Unit, Copenhagen University Hospital, Copenhagen, Denmark. lmi@topotarget.com
Petersen
Kamille Dumong
KD
Persson
Morten
M
Hoff
Kirsten Damgaard
KD
Jensen
Peter Buhl
PB
Sehested
Maxwell
M
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000276:immunology; D006657:Histones / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013449:Sulfonamides; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013449:Sulfonamides; D006655:Histone Deacetylases; C487081:belinostat