Abstract | BACKGROUND: PROCEDURES: RESULTS: In vitro, the IC50 concentration of entinostat ranged from 280 to 1300 nM. In vivo, entinostat significantly inhibited the growth of only Rh10 xenografts. For most studies, entinostat did not potentiate the activity of the cytotoxic agent. Exceptions included the vincristine and entinostat combination for Rh10 and the entinostat and actinomycin D combination for Rh10 and Rh18, although the effects were modest. For Rh18, the combination of entinostat with vincristine showed evidence of an antagonistic interaction compared with single-agent vincristine. Pharmacokinetic studies showed the average Cmax was 569.4 ng/mL (1.51 μM) with Tmax at 15 minutes, and total exposure (AUC0-12 h ) was 435.6 h × ng/mL. Entinostat treatment increased acetylated histone H3. CONCLUSIONS:
Entinostat demonstrated modest antitumor activity in only one of four models at dose and shedule that gave drug exposures relevant to human treatment. The addition of entinostat to standard-of-care cytotoxic agents was in most instances no more effective than the cytotoxic agents used alone. Entinostat demonstrated target inhibition with increased histone 2A acetylation.
|
Authors | Raushan T Kurmasheva, Abhik Bandyopadhyay, Edward Favours, Vanessa Del Pozo, Samson Ghilu, Doris A Phelps, Stephen W Erickson, Cody J Peer, William D Figg, Malcolm A Smith, Peter J Houghton |
Journal | Pediatric blood & cancer
(Pediatr Blood Cancer)
Vol. 66
Issue 8
Pg. e27820
(08 2019)
ISSN: 1545-5017 [Electronic] United States |
PMID | 31099166
(Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)
|
Copyright | © 2019 Wiley Periodicals, Inc. |
Chemical References |
- Benzamides
- Pyridines
- Dactinomycin
- entinostat
- Vincristine
- Cyclophosphamide
|
Topics |
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Apoptosis
(drug effects)
- Benzamides
(administration & dosage)
- Breast Neoplasms
(drug therapy, pathology)
- Cell Proliferation
(drug effects)
- Cyclophosphamide
(administration & dosage)
- Dactinomycin
(administration & dosage)
- Female
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Pyridines
(administration & dosage)
- Standard of Care
- Tumor Cells, Cultured
- Vincristine
(administration & dosage)
- Xenograft Model Antitumor Assays
|