Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program

Peter J. Houghton, Richard Lock, Hernan Carol, Christopher L. Morton, Doris Phelps, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, John M. Maris, Amy W. Wozniak, Yongchuan Gu, William R. Wilson, Malcolm A. Smith

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22 Scopus citations

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 (10nM to 100μM), and PR-104 in vivo using a weekly×6 schedule at its maximum tolerated dose (MTD) of 550mg/kg. Subsequently PR-104 was tested at 270 and 110mg/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 270mg/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.

Original languageEnglish (US)
Pages (from-to)443-453
Number of pages11
JournalPediatric Blood and Cancer
Volume57
Issue number3
DOIs
StatePublished - Sep 1 2011

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Keywords

  • Developmental therapeutics
  • PR-104
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Houghton, P. J., Lock, R., Carol, H., Morton, C. L., Phelps, D., Gorlick, R., Kolb, E. A., Keir, S. T., Reynolds, C. P., Kang, M. H., Maris, J. M., Wozniak, A. W., Gu, Y., Wilson, W. R., & Smith, M. A. (2011). Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 57(3), 443-453. https://doi.org/10.1002/pbc.22921