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 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 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.