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Physico-Chemical Events

(PP007) Fluctuating oxygen in tumors alters tirapazamine pharmacodynamics.

Cardenas-Navia, Laura^*,1, Dewhirst, Mark², ¹ Biomedical Engineering, Durham, NC, USA² Radiation Oncology, Durham, NC, USA

ABSTRACT- Hypoxic cytotoxins have been developed to target tumor cells unresponsive to radiation therapy. Tirapazamine′s (TPZ) pharmacokinetic and pharmacodynamic O₂ dependence has previously been characterized in vitro. This work examines the effects of fluctuating hypoxia in silico on intracellular TPZ concentration using normalized sinusoidal functions for O₂ fluctuations in 1-D. Our results show that the pharmacodynamic effect of TPZ is increased with fluctuating (vs constant) hypoxia at all frequencies (1-30 min period) and magnitudes (1-15 mm Hg). Fluctuating pO₂ has the greatest impact on TPZ pharmacodynamics at the slow frequencies which have been observed in vivo (10-30 min period). Additionally, fluctuating O₂ resulted in more intracellular TPZ near the oxygen source as compared with the steady state condition of the same overall average pO₂. Fluctuating pO₂ reduced the concentration of intracellular 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 hypoxia may need to be taken into account when considering drug designs that involve hypoxic cytotoxicity. This work was supported by grants from DOD BC043284 and the NCI CA40355.

Key words: intermittent hypoxia, tirapazamine, modeling