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. 2011 Sep;57(3):443-53.
doi: 10.1002/pbc.22921. Epub 2010 Dec 27.

Initial Testing of the Hypoxia-Activated Prodrug PR-104 by the Pediatric Preclinical Testing Program

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Free PMC article

Initial Testing of the Hypoxia-Activated Prodrug PR-104 by the Pediatric Preclinical Testing Program

Peter J Houghton et al. Pediatr Blood Cancer. .
Free PMC article

Abstract

Background: PR-104 is rapidly hydrolyzed to PR-104A in vivo, which is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and amine (PR-104M) to produce DNA interstrand cross-links. PR-104 activation can occur via hypoxia-dependent reductases and also independently of hypoxia by aldo-keto reductase (AKR) 1C3.

Procedures: PR-104A was tested against the PPTP in vitro panel (10 nM to 100 µM), and PR-104 in vivo using a weekly × 6 schedule at its maximum tolerated dose (MTD) of 550 mg/kg. Subsequently PR-104 was tested at 270 and 110 mg/kg. Pharmacokinetics for PR-104 and its metabolites were determined, as were levels of AKR1C3 RNA and protein in xenografts.

Results: In vitro, the leukemia models were most sensitive to PR-104A. In vivo, PR-104 induced objective responses at its MTD in 21/34 solid tumor models and maintained complete responses against 7/7 acute lymphoblastic leukemia (ALL) models. At 270 mg/kg and lower dose levels, PR-104 did not induce solid tumor regressions, suggesting a steep dose-response relationship. Pharmacokinetic analysis suggests higher systemic exposures to PR-104A and its metabolites in mice compared to those achievable in patients. Levels of AKR1C3 protein did not correlate with tumor responsiveness.

Conclusions: As monotherapy, PR-104 demonstrated a high level of activity against both solid tumor and ALL models at its MTD, but the activity was almost completely lost at half the MTD dose for solid tumors. Pharmacokinetic data at the PR-104 MTD from human trials suggest that PR-104 metabolites may not reach the plasma exposures in children that were associated with high-level preclinical activity.

Conflict of interest statement

Conflict of interest: William R. Wilson is a shareholder in Proacta, Inc. Yongchuan Gu is an employee of Proacta. The other authors consider that there are no actual or perceived conflicts of interest.

Figures

Fig. 1
Fig. 1
PR-104 in vitro activity. A: Relative sensitivity of the cell lines using the IC50 values displayed by histotype. The black line indicates the median IC50 (16.5 μM) for the panel. Cells were exposed to PR-104 for 96 hr under aerobic conditions at concentrations from 10 nM to 100 μM, and viable cells determined by fluorescein diacetate staining. Concentrations of PR-104 that inhibited cell proliferation by 50% (IC50) are plotted for each cell line of each histotype. B: Typical growth inhibition curves for Rh30 and COG-LL-317. Error bars represent standard deviations for each concentration tested.
Fig. 2
Fig. 2
PR-104 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.
Fig. 3
Fig. 3
PR-104 activity against individual solid tumor xenografts. Kaplan–Meier curves for EFS, median relative tumor volume graphs, and individual tumor volume graphs are shown for selected lines. Controls (gray lines); treated (black lines).
Fig. 4
Fig. 4
PR-104 activity against ALL xenografts. Kaplan–Meier curves for EFS and graphs of median and individual percentages of hCD45 cells, are shown for selected lines. Controls (gray lines); treated (black lines).
Fig. 5
Fig. 5
Dose–response of sarcoma xenografts treated with PR-104. Tumor bearing mice were treated with PR-104 at 550 mg/kg (■), 270 mg/kg (◆), or 110 mg/kg (▼), or received no treatment (●). Curves show the median growth of 10 tumors per dose group.
Fig. 6
Fig. 6
Plasma concentration–time profiles of PR-104 metabolites in scid−/− mice dosed i.p. at 270 mg/kg (466 μmol/kg).
Fig. 7
Fig. 7
AKR1C3 reductase levels. A: Gene expression data obtained from Affymetrix HG-U133 Plus 2.0 for AKR1C3 for PPTP cell lines and xenografts as visualized using GeneSifter software (VizX Labs, Seattle, WA). Gray indicates an absent call from Affymetrix quality control. B: AKR1C3 protein expression levels as determined by Western blotting in selected xenografts.

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