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.
OBJECTIVE
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
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.
McPhail
Lesley D
LD
CRUK Clinical Magnetic Resonance Research Group, The Institute of Cancer Research, Sutton, Surrey, United Kingdom. Lesley.McPhail@icr.ac.uk
Griffiths
John R
JR
Robinson
Simon P
SP
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009369:Neoplasms / Q000097:blood / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D051381:Rats; D011920:Rats, Inbred WF; D013267:Stilbenes / Q000627:therapeutic use*; D044004:Xanthones / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D006454:Hemoglobins; D013267:Stilbenes; D044004:Xanthones; C066668:vadimezan; C100003:deoxyhemoglobin; C058728:fosbretabulin