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. 2014 Feb;61(2):245-52.
doi: 10.1002/pbc.24724. Epub 2013 Sep 4.

Initial Testing (Stage 1) of the Histone Deacetylase Inhibitor, Quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program

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Free PMC article

Initial Testing (Stage 1) of the Histone Deacetylase Inhibitor, Quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program

Hernan Carol et al. Pediatr Blood Cancer. .
Free PMC article

Abstract

Background: Quisinostat (JNJ-26481585) is a second-generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs.

Procedures: Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP in vivo panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily × 21.

Results: In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2 nM (range <1-19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease.

Conclusions: Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts.

Keywords: HDAC inhibitor; developmental therapeutics; preclinical testing.

Conflict of interest statement

Conflict of interest statement: The authors consider that there are no actual or perceived conflicts of interest.

Figures

Figure 1
Figure 1
Quisinostat in vivo objective response activity, left: The colored heat map depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥2 but <6, and low activity by a score of <2. Right: representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.
Figure 2
Figure 2
Quisinostat activity in vivo against individual solid tumor xenografts. Kaplan-Meier curves showing the probability for EFS (left), relative tumor volume (center), and individual tumor volumes (right) graphs are shown for selected xenografts (Rh28, D456, and D645). Controls (gray lines); Treated (black lines), significances of the difference between treated and control groups are included.
Figure 3
Figure 3
Quisinostat activity in vivo against individual ALL xenografts. Kaplan-Meier curves showing the probability for EFS (left), median leukemia engraftment (center) as detected in peripheral blood (see Materials and Methods), and individual leukemia engraftment (right) graphs are shown for selected xenografts (ALL-2, ALL-3, ALL-8, and ALL19). Controls (gray lines); Treated (black lines), significances of the difference between treated and control groups are included.

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