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Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions.

Publication ,  Journal Article
Cárdenas-Navia, LI; Secomb, TW; Dewhirst, MW
Published in: Int J Radiat Oncol Biol Phys
February 1, 2007

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.

Duke Scholars

Published In

Int J Radiat Oncol Biol Phys

DOI

ISSN

0360-3016

Publication Date

February 1, 2007

Volume

67

Issue

2

Start / End Page

581 / 586

Location

United States

Related Subject Headings

  • Triazines
  • Tirapazamine
  • Time Factors
  • Partial Pressure
  • Oxygen
  • Oncology & Carcinogenesis
  • Models, Biological
  • Cell Survival
  • Cell Hypoxia
  • Antineoplastic Agents
 

Citation

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ICMJE
MLA
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Cárdenas-Navia, L. I., Secomb, T. W., & Dewhirst, M. W. (2007). Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions. Int J Radiat Oncol Biol Phys, 67(2), 581–586. https://doi.org/10.1016/j.ijrobp.2006.10.002
Cárdenas-Navia, L Isabel, Timothy W. Secomb, and Mark W. Dewhirst. “Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions.Int J Radiat Oncol Biol Phys 67, no. 2 (February 1, 2007): 581–86. https://doi.org/10.1016/j.ijrobp.2006.10.002.
Cárdenas-Navia LI, Secomb TW, Dewhirst MW. Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions. Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):581–6.
Cárdenas-Navia, L. Isabel, et al. “Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions.Int J Radiat Oncol Biol Phys, vol. 67, no. 2, Feb. 2007, pp. 581–86. Pubmed, doi:10.1016/j.ijrobp.2006.10.002.
Cárdenas-Navia LI, Secomb TW, Dewhirst MW. Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions. Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):581–586.
Journal cover image

Published In

Int J Radiat Oncol Biol Phys

DOI

ISSN

0360-3016

Publication Date

February 1, 2007

Volume

67

Issue

2

Start / End Page

581 / 586

Location

United States

Related Subject Headings

  • Triazines
  • Tirapazamine
  • Time Factors
  • Partial Pressure
  • Oxygen
  • Oncology & Carcinogenesis
  • Models, Biological
  • Cell Survival
  • Cell Hypoxia
  • Antineoplastic Agents