In Vivo Assessment of Antiangiogenic Activity of SU6668 in an Experimental Colon Carcinoma Model

Abstract

Purpose: The purpose of this research was to assess in vivo by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) the antiangiogenic effect of SU6668, an oral, small molecule inhibitor of the angiogenic receptor tyrosine kinases vascular endothelial growth factor receptor 2 (Flk-1/KDR), platelet-derived growth factor receptor, and fibroblast growth factor receptor 1.Experimental Design: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. DCE-MRI with a macromolecular contrast agent was used to measure transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. CD31 immunohistochemical staining was used for assessing microvessels density and vessels area. Experiments were performed after 24 h, and 3, 7, and 14 days of treatment.Results: DCE-MRI clearly detected the early effect (after 24 h of treatment) of SU6668 on tumor vasculature as a 51% and 26% decrease in the average vessel permeability measured in the tumor rim and core (respectively). A substantial decrease was also observed in average fractional plasma volume in the rim (59%) and core (35%) of the tumor. Histological results confirmed magnetic resonance imaging findings. After 3, 7, and 14 days of treatment, postcontrast magnetic resonant images presented a thin strip of strongly enhanced tissue at the tumor periphery; histology examination showed that this hyperenhanced ring corresponded to strongly vascularized tissue adjacent but external to the tumor. Histology also revealed a strong decrease in the thickness of peripheral viable tissue, with a greatly reduced vessel count. SU6668 greatly inhibited tumor growth, with 60% inhibition at 14 days of treatment.Conclusions: DCE-MRI detected in vivo the antiangiogenic efficacy of SU6668.

Visual MRI: Merging information visualization and non-parametric clustering techniques for MRI dataset analysis

“…The dynamic evolution of the signal intensity in MR images is analyzed using a two compartments tissue model [30], in which the contrast agent can freely diffuse between plasma and interstitial space. k PS and f PV values are obtained pixel by pixel by fitting the theoretical expression to experimental data [20]. In this work experiments were performed in order to assess the antiangiogenic effect of a specific drug.…”

“…In this work experiments were performed in order to assess the antiangiogenic effect of a specific drug. Data analysis was adapted from [30] for the special case of a macromolecular contrast agent [20].…”

“…This phase realizes a straight linked brushing (from physical space to parameter space). are characterized by an external well-vascularized rim, composed by a viable tumor tissue, and by an internal, scarcely vascularized necrotic area [20].…”

“…For this reason, human computer interaction and information visualization (IV) [3] methodologies have been proven to be very useful in supporting physicians in decision-based activities, such as those related to diagnoses and therapies. Furthermore, when dealing with a huge amount of data, automatic techniques for the reduction and simplification of the given data set as well as for the recognition of relevant patterns are needed: several kinds of data mining (DM) techniques have been proposed to deal with trast Enhanced MRI (DCE-MRI) techniques play a relevant role in this field [19,20]. DCE-MRI with macromolecular contrast agents has been used to measure characteristics of tumor microvessels such as transendothelial permeability (kPS) and fractional plasma volume (f PV) that are accepted surrogate markers of tumor angiogenesis [19].…”

Towards Information Visualization and Clustering Techniques for MRI Data Sets

“…In this paper we aim at integrating the use of Information Visualization (IV) techniques and data mining algorithms for the analysis of Magnetic Resonance Imaging (MRI) data sets. Preclinical and clinical evaluation of the efficacy of antiangiogenic compounds poses new problems to researchers because the traditional criterion for assessing the response of a tumor to a treatment, based on the measurement of tumor size reduction, is no longer valid [3]. Dynamic Contrast Enhanced MRI (DCE-MRI) techniques play a relevant role in this field [3].…”