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

Authors' Affiliations: ¹ Department of Basic Medical Sciences, St. George's Hospital Medical School and ² Antisoma Research, Ltd., London, United Kingdom

Requests for reprints: Lesley McPhail, Department of Basic Medical Sciences, St. Georges Hospital Medical School, Cranmer Terrace, Tooting, SW17 ORE London, United Kingdom. Phone: 44-208-725-5809; Fax: 44-208-725-2992; E-mail: lesley{at}sghms.ac.uk.

Purpose: To use ³¹P and ¹H 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 ³¹P and ¹H MRS measurements of (a) tumor bioenergetics [ß-nucleoside triphosphate/inorganic phosphate (ß-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 ³¹P and ¹H MRS of extracts to provide validation of the in vivo MRS data, histologic analysis of necrosis, and high-performance liquid chromatography.

Results: Both ß-NTP/Pi and PDE/PME decreased in a dose-dependent manner 6 hours posttreatment with DMXAA, with significant decreases in ß-NTP/Pi with 15 mg/kg (P < 0.001) and 21 mg/kg (P < 0.01). A significant decrease in total choline in vivo was found 24 hours posttreatment with 21 mg/kg DMXAA (P < 0.05); this was associated with a significant reduction in the concentration of the membrane degradation products glycerophosphoethanolamine and glycerophosphocholine measured in tissue extracts (P < 0.05).

Conclusions: The reduction in tumor energetics and membrane turnover is consistent with the vascular-disrupting activity of DMXAA. ³¹P MRS revealed tumor response to DMXAA at doses below the maximum tolerated dose for mice. Both ³¹P and ¹H MRS provide biomarkers of tumor response to DMXAA that could be used in clinical trials.

Key Words: DMXAA • MRS • vascular-targeting • choline metabolism