Assessment of tumor response to the vascular disrupting agents 5,6-dimethylxanthenone-4-acetic acid or combretastatin-A4-phosphate by intrinsic susceptibility magnetic resonance imaging.

Abstract

PURPOSE:

To investigate the use of the transverse magnetic resonance imaging (MRI) relaxation rate R(2)(*) (s(-1)) as a biomarker of tumor vascular response to monitor vascular disrupting agent (VDA) therapy.

METHODS AND MATERIALS:

Multigradient echo MRI was used to quantify R(2)(*) in rat GH3 prolactinomas. R(2)(*) is a sensitive index of deoxyhemoglobin in the blood and can therefore be used to give an index of tissue oxygenation. Tumor R(2)(*) was measured before and up to 35 min after treatment, and 24 h after treatment with either 350 mg/kg 5,6-dimethylxanthenone-4-acetic acid (DMXAA) or 100 mg/kg combretastatin-A4-phosphate (CA4P). After acquisition of the MRI data, functional tumor blood vessels remaining after VDA treatment were quantified using fluorescence microscopy of the perfusion marker Hoechst 33342.

RESULTS:

DMXAA induced a transient, significant (p < 0.05) increase in tumor R(2)(*) 7 min after treatment, whereas CA4P induced no significant changes in tumor R(2)(*) over the first 35 min. Twenty-four hours after treatment, some DMXAA-treated tumors demonstrated a decrease in R(2)(*), but overall, reduction in R(2)(*) was not significant for this cohort. Tumors treated with CA4P showed a significant (p < 0.05) reduction in R(2)(*) 24 h after treatment. The degree of Hoechst 33342 uptake was associated with the degree of R(2)(*) reduction at 24 h for both agents.

CONCLUSIONS:

The reduction in tumor R(2)(*) or deoxyhemoglobin levels 24 h after VDA treatment was a result of reduced blood volume caused by prolonged vascular collapse. Our results suggest that DMXAA was less effective than CA4P in this rat tumor model.

• Authors: Lesley D McPhail, John R Griffiths, Simon P Robinson
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 69 Issue 4 Pg. 1238-45 (Nov 15 2007) ISSN: 0360-3016 [Print] United States
• PMID: 17967313 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Biomarkers, Tumor
• Hemoglobins
• Stilbenes
• Xanthones
• vadimezan
• deoxyhemoglobin
• fosbretabulin

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Biomarkers, Tumor (metabolism)
• Female
• Hemoglobins (metabolism)
• Magnetic Resonance Imaging (methods)
• Neoplasms (blood, blood supply, drug therapy)
• Neovascularization, Pathologic (drug therapy)
• Rats
• Rats, Inbred WF
• Stilbenes (therapeutic use)
• Xanthones (therapeutic use)