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

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 R2*, but overall, reduction in R-2* was not significant for this cohort. Tumors treated with CA4P showed a significant (p < 0.05) reduction in R2* 24 It 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. @ 2007 Elsevier Inc.