Tumor dose response to the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid, using in vivo magnetic resonance spectroscopy.
OBJECTIVE
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.


METHODS
In vivo (31)P and (1)H MRS measurements of (a) tumor bioenergetics [beta-nucleoside triphosphate/inorganic phosphate (beta-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 beta-NTP/Pi and PDE/PME decreased in a dose-dependent manner 6 hours posttreatment with DMXAA, with significant decreases in beta-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. (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.
McPhail
Lesley D
LD
Department of Basic Medical Sciences, St. George's Hospital Medical School and Antisoma Research, Ltd., London, United Kingdom.
Chung
Yuen-Li
YL
Madhu
Basetti
B
Clark
Simon
S
Griffiths
John R
JR
Kelland
Lloyd R
LR
Robinson
Simon P
SP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D014183:Transplantation, Heterologous; D044004:Xanthones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan