title: 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.
authors.affiliation: Department of Cancer Biology 164, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Mukund.Seshadri@roswellpark.org
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciesielski
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002533:Cerebral Angiography; D003287:Contrast Media; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D044004:Xanthones / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D044004:Xanthones; C066668:vadimezan