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.
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.
Authors: Jenghwa Chang; Bixiu Wen; Peter Kazanzides; Pat Zanzonico; Ronald D Finn; Gabor Fichtinger; C Clifton Ling Journal: Med Phys Date: 2009-11 Impact factor: 4.071
Authors: Arup Bhattacharya; Károly Tóth; Farukh A Durrani; Shousong Cao; Harry K Slocum; Sreenivasulu Chintala; Youcef M Rustum Journal: Neoplasia Date: 2008-08 Impact factor: 5.715
Authors: Ashley A Manzoor; Lars H Lindner; Chelsea D Landon; Ji-Young Park; Andrew J Simnick; Matthew R Dreher; Shiva Das; Gabi Hanna; Won Park; Ashutosh Chilkoti; Gerben A Koning; Timo L M ten Hagen; David Needham; Mark W Dewhirst Journal: Cancer Res Date: 2012-09-04 Impact factor: 12.701
Authors: Annika Foehrenbacher; Kashyap Patel; Maria R Abbattista; Chris P Guise; Timothy W Secomb; William R Wilson; Kevin O Hicks Journal: Front Oncol Date: 2013-10-07 Impact factor: 6.244
Authors: Axel R Pries; Annemiek J M Cornelissen; Anoek A Sloot; Marlene Hinkeldey; Matthew R Dreher; Michael Höpfner; Mark W Dewhirst; Timothy W Secomb Journal: PLoS Comput Biol Date: 2009-05-29 Impact factor: 4.475