Evaluation of tumor ischemia in response to an indole-based vascular disrupting agent using BLI and (19)F MRI.

Vascular disrupting agents (VDAs) have been proposed as an effective broad spectrum approach to cancer therapy, by inducing ischemia leading to hypoxia and cell death. A novel VDA (OXi8007) was recently reported to show rapid acute selective shutdown of tumor vasculature based on color-Doppler ultrasound. We have now expanded investigations to noninvasively assess perfusion and hypoxiation of orthotopic human MDA-MB-231/luc breast tumor xenografts following the administration of OXi8007 based on dynamic bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). BLI showed significantly lower signal four hours after the administration of OXi8007, which was very similar to the response to combretastatin A-4P (CA4P), but the effect lasted considerably longer, with the BLI signal remaining depressed at 72 hrs. Meanwhile, control tumors exhibited minimal change. Oximetry used F-19 MRI of the reporter molecule hexafluorobenzene and FREDOM (Fluorocarbon Relaxometry using Echo Planar Imaging for Dynamic Oxygen Mapping) to assess pO(2) distributions during air and oxygen breathing. pO(2) decreased significantly upon the administration of OXi8007 during oxygen breathing (from 122 +/- 64 to 34 +/- 20 Torr), with further decrease upon switching the gas to air (pO(2) = 17 +/- 9 Torr). pO(2) maps indicated intra-tumor heterogeneity in response to OXi8007, though ultimately all tumor regions became hypoxic. Both BLI and FREDOM showed the efficacy of OXi8007. The pO(2) changes measured by FREDOM may be crucial for future study of combined therapy.