title: Oxygen dependence and extravascular transport of hypoxia-activated prodrugs: comparison of the dinitrobenzamide mustard PR-104A and tirapazamine.
abstract: OBJECTIVE
  To compare oxygen dependence and tissue transport properties of a new hypoxia-activated prodrug, PR-104A, with tirapazamine, and to evaluate the implications for antitumor activity when combined with radiotherapy.
  
  
  METHODS
  Oxygen dependence of cytotoxicity was measured by clonogenic assay in SiHa cell suspensions. Tissue transport parameters were determined using SiHa multicellular layers. Spatially resolved pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to predict cell killing in SiHa tumors and tested by clonogenic assay 18 h after treatment with the corresponding phosphate ester, PR-104.
  
  
  RESULTS
  The K-value (oxygen concentration to halve cytotoxic potency) of PR-104A was 0.126 +/- 0.021 microM (10-fold lower than tirapazamine at 1.30 +/- 0.28 microM). The diffusion coefficient of PR-104A in multicellular layers (4.42 +/- 0.15 x 10(-7) cm2 s(-1)) was lower than that of tirapazamine (1.30 +/- 0.05 x 10(-6) cm2 s(-1)) but PK modeling predicted better penetration to hypoxic cells in tumors because of its slower metabolism. The tirapazamine PK/PD model successfully predicted the measured activity in combination with single-dose radiation against SiHa tumors, and the PR-104A model underpredicted the activity, which was greater for PR-104 than for tirapazamine (at equivalent host toxicity) both with radiation and as a single agent.
  
  
  CONCLUSIONS
  PR-104/PR-104A has different PK/PD properties from tirapazamine and superior activity with single-dose radiotherapy against SiHa xenografts. We have inferred that PR-104A is better able to kill cells at intermediate partial pressure of oxygen in tumors than implied by the PK/PD model, most likely because of a bystander effect resulting from diffusion of its activated metabolites from severely hypoxic zones.
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland School of Medical Sciences, Auckland, New Zealand. k.hicks@auckland.ac.nz
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Hicks
authors.forename: Hilary
authors.initials: H
authors.lastname: Myint
authors.forename: Adam V
authors.initials: AV
authors.lastname: Patterson
authors.forename: Frederik B
authors.initials: FB
authors.lastname: Pruijn
authors.forename: Bronwyn G
authors.initials: BG
authors.lastname: Siim
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D015687:Cell Hypoxia / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics*; D010100:Oxygen / Q000502:physiology*; D010313:Partial Pressure; D011355:Prodrugs / Q000493:pharmacokinetics*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D000077704:Tirapazamine; D014227:Triazines / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; C524170:PR-104A; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D010100:Oxygen