Belinostat (PXD101) is a novel HDAC inhibitor with an IC50 of 27 nM. Belinostat (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. This hdac inhibitor is currently under phase I/II testing in lymphoma, ovarian cancer and other solid tumors.
|Cell lines||A2780, A2780/cp70, CALU-3, MCF7, PC3, HS852, HT29 and HCT116 cell lines|
|Preparation method||Cytotoxicity Assay.
Drug sensitivity was determined by a clonogenic assay (13). Briefly, cells were plated in 5 ml of medium at a density of 8 × 104 cells/25 cm2 flask and allowed to attach and grow for 48 h. Cells were exposed to drug (five concentrations from 0.016 to 10 μM) for 24 h. The medium was removed, and 1 ml of trypsin/EDTA was added to each flask. Once the cells had detached, 1 ml of medium was added, the cells were resuspended, and those from the control untreated flask were counted. Cells were diluted and plated into 6-cm Petri dishes (three per flask) at a density of 500-2000 cells/dish depending on the cell line. Cells from the drug-treated flasks were diluted and plated as for the control flasks. Dishes were incubated for 10–15 days at 37°C. Cells were washed with PBS, fixed in methanol, and stained with crystal violet, and colonies that contained ≥50 cells counted. Sensitivity is expressed as the IC50 (mean ± SE of three experiments) defined as the concentration of drug required to reduce the number of colonies to 50% of that of the control untreated cells.
|Concentrations||0.016 ~ 10 μM|
|Incubation time||24 h|
|Animal models||A2780, A2780/cp70 and HCT116 tumor-bearing mice model|
|Formulation||dissolved in DMSO and then diluted in water to give a final concentration of DMSO of 10%|
|Dosages||a single injection of 40 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group.
Yeo W, et al. J Clin Oncol. 2012 Sep 20;30(27):3361-7. PMID: 22915658.
Phase II activity of belinostat (PXD-101), carboplatin, and paclitaxel in women with previously treated ovarian cancer.
Dizon et al. Int J Gynecol Cancer. 2012 Jul;22(6):979-86. PMID: 22694911.
Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer.
Dovzhanskiy et al. BMC Cancer. 2012 Jun 8;12:226. PMID: 22681698.
A phase II evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study.
Dizon et al. Gynecol Oncol. 2012 May;125(2):367-71. PMID: 22366594.
Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models.
Gravina et al. Int J Oncol. 2012 Mar;40(3):711-20. PMID: 22134754.
Belinostat: clinical applications in solid tumors and lymphoma.
Molife et al. Expert Opin Investig Drugs. 2011 Dec;20(12):1723-32. PMID: 22046971.
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