Abstract 649: Dynamic magnetic resonance imaging of the effects of vascular targeting agents on intracerebral metastases

Abstract

Abstract Objective: Agents that target tumor vasculature are gaining use as therapeutics for brain tumors. We used dynamic magnetic resonance imaging (MRI) to evaluate the vascular effects of the monoclonal antibodies bevacizumab, targeting vascular endothelial growth factor (VEGF), and intetumumab (CNTO 95), targeting αV integrins, in a rat model of lung cancer brain metastasis. Methods: Female nude rats received intracerebral implantation of human LX-1 small cell lung carcinoma cells. At 10 days after tumor implantation, rats were untreated or treated with intetumumab (30 mg/kg IV) or bevacizumab (45 mg/kg IV) (n = 4-5 per group). MRI at 12T was performed prior to treatment and at 1, 3, and 7 days after treatment, using dynamic contrast enhanced (DCE) MRI with gadolinium-based contrast agent (GBCA), and dynamic susceptibility contrast (DSC) MRI with the blood pool iron oxide nanoparticle ferumoxytol. Tumor relative cerebral blood volume (rCBV) and permeability markers were assessed. Results: Intetumumab increased brain tumor vascular permeability at 3 and 7 days after treatment on DCE-MRI, as determined by the ratio of maximum GBCA signal intensity to normal brain, a measure of the interstitial space volume fraction (ve), and time to peak enhancement, a surrogate for Ktrans, the rate constant for passive leakage across the blood-brain barrier. Intetumumab also increased tumor rCBV on DSC-MRI as compared to untreated controls. Tumors uniformly grew during the week assessment period. In contrast, bevacizumab decreased tumor permeability and rCBV, and slowed the increase in the volume of enhancing tumor on both T1-weighted and T2-weighted images, compared with controls. Conclusions: The vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in a rat brain metastasis model. The αV integrin inhibitory antibody intetumumab appeared to increase tumor vascular permeability and blood volume, suggesting it may enhance chemotherapy efficacy by improving chemotherapy delivery to intracerebral tumors. Conversely, the effects of bevacizumab on tumor vasculature suggest it would actually decrease chemotherapy delivery, thereby minimizing chemotherapy efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 649.