MRI-Based Characterization of Vascular Disruption by 5,6-Dimethylxanthenone-Acetic Acid in Gliomas

Abstract

The well-vascularized nature of gliomas has generated a lot of interest in antiangiogenic therapies. However, the potential of vascular disrupting agents (VDAs) against gliomas has not been investigated extensively. In this study, we examined the in vivo efficacy of the tumor-VDA 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against gliomas. Contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted MRI were used to characterize the vascular and cellular responses of GL261 and U87 gliomas to DMXAA treatment. Therapeutic efficacy was assessed by Kaplan-Meier survival analysis. Before VDA treatment, minimal enhancement was detected within the tumor in both models. Longitudinal relaxation rate (R1=1/T1) maps acquired 24 h after treatment showed marked extravasation and accumulation of the contrast agent in the tumor indicative of treatment-induced vascular disruption. Normalized change in relaxation rate (DeltaR1) values of the tumor showed a significant increase (P<0.01 GL261; P<0.05 U87) after therapy compared with baseline estimates. Mean apparent diffusion coefficient (ADC) values were significantly increased (P=0.015) 72 h after therapy in GL261 but not in U87 gliomas. Vascular disrupting agent therapy resulted in a significant (P<0.01) increase in median survival in both models evaluated. The results highlight the potential of VDAs against gliomas and the utility of MRI in the assessment of glioma response to VDA therapy.