Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions

L. Isabel Cárdenas-Navia, Timothy W. Secomb, Mark W. Dewhirst

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Purpose: To examine the effects of fluctuating oxygen levels on the hypoxic cytotoxin tirapazamine (TPZ) using theoretical predictions. Methods: and Materials Tirapazamine's pharmacokinetic and pharmacodynamic oxygen dependence has previously been characterized in vitro. Here, a one-dimensional theoretical model was used to examine the effects of fluctuating hypoxia on metabolized TPZ concentration, assuming sinusoidally fluctuating oxygen levels. TPZ concentration is changing according to published experimental data. Simulations of experimentally observed time-courses of perivascular pO2 were also conducted. Results: The predicted pharmacodynamic effect of TPZ was increased with fluctuating (vs. constant) hypoxia at all frequencies (1-30 min period) and all amplitudes (1-15 mm Hg). Additionally, fluctuating oxygen resulted in more metabolized TPZ near the oxygen source as compared with the steady-state condition of the same overall average pO2. Conclusions: Fluctuating pO2 reduced the concentration of metabolized TPZ at distances farther from the source, thereby limiting its ability to reach and kill the most hypoxic cells. These results suggest that the kinetics of fluctuating oxygenation should be taken into account when considering drug designs that involve oxygen-sensitive agents.

Original languageEnglish (US)
Pages (from-to)581-586
Number of pages6
JournalInternational Journal of Radiation Oncology Biology Physics
Volume67
Issue number2
DOIs
StatePublished - Feb 1 2007

Keywords

  • Fluctuating hypoxia
  • Hypoxic cytotoxins
  • Tirapazamine

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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