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

Abstract

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 [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.

• Authors: Lesley D McPhail, Yuen-Li Chung, Basetti Madhu, Simon Clark, John R Griffiths, Lloyd R Kelland, Simon P Robinson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 10 Pg. 3705-13 (May 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15897567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Xanthones
• vadimezan

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma (drug therapy, metabolism)
• Cell Membrane (metabolism)
• Colonic Neoplasms (drug therapy, metabolism)
• Dose-Response Relationship, Drug
• Energy Metabolism
• Magnetic Resonance Spectroscopy
• Male
• Mice
• Mice, Nude
• Neovascularization, Pathologic
• Transplantation, Heterologous
• Xanthones (pharmacology)