Plasma and CSF concentrations of belinostat were quantified with an LC/MS/MS assay. Pharmacokinetic parameters were calculated using non compartmental methods, and CSF penetration is expressed as the ratio of the area under the concentration time curve in CSF to the AUC in plasma.Histones are chromatin proteins packaged with DNA in the nucleosome. Danoprevir Modification of these histone proteins plays a fundamental role in regulating gene expression . Acetylation and deacetylation of histones is controlled by the activities of histone acetyltransferases and histone deacetylases , respectively. Deacetylation of histones is associated with condensation of chromatin and repression of gene transcription, and aberrant HDAC activity may be associated with tumor formation .
Inhibition of HDAC has been shown to induce expression of genes associated with cell cycle arrest and tumor suppression . HDAC inhibitors are being investigated as antitumor agents for a variety of cancers. There is interest in evaluating Ofloxacin molecular weight HDAC inhibitors in Rivaroxaban price patients with CNS tumors because of reports of in vitro activity in glioma cell lines . Belinostat is a low molecular weight HDAC inhibitor with activity in vitro against human tumor cell lines, and in vivo against human tumor xenografts . Histone deacetylase enzyme activity in cell lysates is inhibited by belinostat at IC50 values of 9100 nM . Belinostat is currently being evaluated in a number of Phase Ib/II combination and Phase II monotherapy clinical trials for solid tumors and hematologic malignancies.
CNS tumors are difficult to treat, in part, due to the presence of the blood: brain barrier , which is comprised of brain capillary endothelial cells that restrict entry of anticancer agents into the CNS. Determining the penetration of drugs into the CSF is used as a surrogate for DNA-PK ligand BBB penetration and is useful for identifying agents that may prove useful for treating CNS tumors. A non human primate model has been used to quantify CSF drug penetration after systemic administration and has been highly predictive of CNS pharmacology in humans . We studied the CSF penetration of the HDAC inhibitor, belinostat, in this animal model.Belinostat was supplied by the investigational drug branch of the Cancer Therapy Evaluation Program , NCI as a powder, and reconstituted with L arginine 100 mg/ml to prepare an intravenous formulation just prior to infusion.
carbohydrates Belinostat was administered via a central catheter as a 30 min infusion at escalating doses of 1060 mg/kg . Non human primate model Five adult male rhesus monkeys weighing 11.213.7 kg were used for the study. The animals were fed NIH open formula extruded non human primate diet and group housed indoors in accordance with the Guide for the Care and Use of Laboratory Animals . Blood for pharmacokinetic sampling was obtained via a temporary saphenous venous catheter. For CSF sampling, the initial animal had a temporary lumbar catheter. The remaining four animals had a pudenz catheter permanently implanted in the 4th ventricle and attached to a subcutaneous Ommaya reservoir, which allows for repeated CSF sampling in unanesthetized animals . Pharmacokinetic sampling Blood was collected in heparinized tubes prior to the dose of belinostat, at the completion of the infusion.