Publications [#63293] of Mark W. Dewhirst

Papers Published

1. Cardenas-Navia, L. Isabel and Secomb, Timothy W. and Dewhirst, Mark W., Effects of fluctuating oxygenation on tirapazamine efficacy: Theoretical predictions, International Journal of Radiation Oncology Biology Physics, vol. 67 no. 2 (2007), pp. 581 - 586 [002]
   (last updated on 2007/04/14)

   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. © 2007 Elsevier Inc. All rights reserved.

   Keywords:
   Computer simulation;Natural frequencies;Oxygen;Oxygenators;Patient treatment;