Tumor Dose Response to the Vascular Disrupting Agent, 5,6-Dimethylxanthenone-4-Acetic Acid, Using In vivo Magnetic Resonance Spectroscopy

Purpose: To use 31 P and 1 H magnetic resonance spectroscopy (MRS) to assess changes in tumor metabolic profile in vivo in response to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with a view to identifying biomarkers associated with tumor dose response. Experimental Design: In vivo 31 P and 1 H MRS measurements of ( a ) tumor bioenergetics [β-nucleoside triphosphate/inorganic phosphate (β-NTP/Pi)], ( b ) the membrane-associated phosphodiesters and phosphomonoesters (PDE/PME), ( c ) choline (mmol/L), and ( d ) lactate/water ratio were made on murine HT29 colon carcinoma xenografts pretreatment and 6 or 24 hours posttreatment with increasing doses of DMXAA. Following in vivo MRS, the tumors were excised and used for high-resolution 31 P and 1 H MRS of extracts to provide validation of the in vivo MRS data, histologic analysis of necrosis, and high-performance liquid chromatography. Results: Both β-NTP/Pi and PDE/PME decreased in a dose-dependent manner 6 hours posttreatment with DMXAA, with significant decreases in β-NTP/Pi with 15 mg/kg ( P P in vivo was found 24 hours posttreatment with 21 mg/kg DMXAA ( P P Conclusions: The reduction in tumor energetics and membrane turnover is consistent with the vascular-disrupting activity of DMXAA. 31 P MRS revealed tumor response to DMXAA at doses below the maximum tolerated dose for mice. Both 31 P and 1 H MRS provide biomarkers of tumor response to DMXAA that could be used in clinical trials.