title: Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program.
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.
  
  
  METHODS
  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.
authors: Nationwide Children's Hospital, Columbus, OH, USA. peter.houghton@nationwidechildrens.org
authors: Peter J
authors: PJ
authors: Houghton
authors: Richard
authors: R
authors: Lock
authors: Hernan
authors: H
authors: Carol
authors: Christopher L
authors: CL
authors: Morton
authors: Doris
authors: D
authors: Phelps
authors: Richard
authors: R
authors: Gorlick
authors: E Anders
authors: EA
authors: Kolb
authors: Stephen T
authors: ST
authors: Keir
authors: C Patrick
authors: CP
authors: Reynolds
authors: Min H
authors: MH
authors: Kang
authors: John M
authors: JM
authors: Maris
authors: Amy W
authors: AW
authors: Wozniak
authors: Yongchuan
authors: Y
authors: Gu
authors: William R
authors: WR
authors: Wilson
authors: Malcolm A
authors: MA
authors: Smith
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D009588:Nitrogen Mustard Compounds; C522381:PR-104; C524170:PR-104A; D011355:Prodrugs