MRI-based characterization of vascular disruption by 5,6-dimethylxanthenone-acetic acid in gliomas
Mukund Seshadri1, Michael J Ciesielski
1Department of Cancer Biology 164, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Mukund.Seshadri@roswellpark.org
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.
Insights
Vascular disrupting agents (VDAs) show promise in treating gliomas by disrupting tumor blood vessels. This study demonstrates that 5,6-dimethylxanthenone-4-acetic acid (DMXAA) significantly improves survival in glioma models, highlighting VDA potential.
Area of Science:
- Oncology
- Radiology
- Pharmacology
Background:
- Gliomas are highly vascular tumors, making them targets for anti-angiogenic therapies.
- The efficacy of vascular disrupting agents (VDAs) in gliomas remains underexplored.
- 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a tumor-VDA with potential against gliomas.
Purpose of the Study:
- To investigate the in vivo efficacy of DMXAA against gliomas.
- To characterize the vascular and cellular responses to DMXAA using MRI.
- To assess the therapeutic impact of DMXAA on glioma survival.
Main Methods:
- Utilized contrast-enhanced and diffusion-weighted MRI to evaluate GL261 and U87 glioma models.
- Assessed vascular disruption via longitudinal relaxation rate (R1) changes post-DMXAA.
- Measured cellular changes using apparent diffusion coefficient (ADC) values.
- Determined therapeutic efficacy using Kaplan-Meier survival analysis.
Main Results:
- DMXAA treatment induced significant vascular disruption, evidenced by contrast agent extravasation and increased R1 values.
- Apparent diffusion coefficient (ADC) values increased significantly in GL261 gliomas 72 hours post-treatment.
- DMXAA therapy significantly improved median survival in both GL261 and U87 glioma models (P<0.01).
Conclusions:
- Vascular disrupting agents (VDAs) demonstrate significant therapeutic potential against gliomas.
- MRI is a valuable tool for assessing glioma response to VDA therapy.
- DMXAA shows promise as a VDA for glioma treatment.