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

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. 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. 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. 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.