Magnetic resonance imaging for monitoring the effects of thalidomide on experimental human breast cancers

Abstract

Thalidomide, which inhibits angiogenesis in certain tumor types, reduced extravasation of a macromolecular contrast medium (MMCM) in a human breast cancer model as assayed by MMCM-enhanced dynamic magnetic resonance imaging (MRI) and fluorescence microscopy in the same tumors. After a 1-week, three-dose course of thalidomide, the mean MRI-assayed endothelial transfer coefficient, KPS, decreased significantly (p<0.05) from 19.4±9.1 to 6.3±9.1 μl/min·100 cm3. Correspondingly, microscopic measurements of extravasated MMCM, expressed as fractional area of streptavidin staining, were significantly (p<0.05) lower in thalidomide-treated tumors (18.6±11.9%) than in control saline-treated tumors (50.2±2.3%). On a tumor-by-tumor basis, post-treatment KPS values correlated significantly (r2=0.55, p<0.05) with microscopic measures of MMCM extravasation. However, no significant differences were observed between saline- and thalidomide-treated tumors with respect to rate of growth, vascular richness, or amount of VEGF-containing cells. Because of its sensitivity to the detection of changes in vascular leakage in tumors, this MMCM-enhanced MRI assay could prove useful for monitoring the effects of thalidomide on an individual patient basis. The significant correlation between MRI and fluorescence microscopic measures of MMCM extravasation supports the utility of the non-invasive MRI approach for assessing the action of thalidomide on tumor blood vessels.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) in Preclinical Studies of Antivascular Treatments

“…Thalidomide has been investigated in different scenarios [ 107 , 108 , 109 ]. One study found reduced vessel permeability for a macromolecular contrast agent as a result of vascular normalization [ 108 ], while another study found increased blood plasma volume fraction [ 107 ].…”

Perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging predict outcomes of hepatocellular carcinoma receiving radiotherapy with or without thalidomide

“…With a priori DCEMRI study in HCC patients receiving RT, we evaluated the combination effect of thalidomide to RT within the same population of patients with identical image acquisition and analysis protocols. Preclinical studies revealed a significantly reduced extravasation of contrast medium and decreased endothelial transfer coefficient (K ps ) of MRI 7 days after thalidomide (100 mg/kg) [26]. The best timing of radiation sensitization by thalidomide demonstrated in preclinical study was administering thalidomide (200 mg/kg) 2 days before RT when an increased initial slope and peak enhancement of the DCEMRI study with enhanced perfusion, reduced interstitial fluid pressure, and reoxygenation of mouse tumors were found [27].…”

Permeability to macromolecular contrast media quantified by dynamic MRI correlates with tumor tissue assays of vascular endothelial growth factor (VEGF)

“…Earlier studies have shown that dynamic MRI enhanced with macromolecular contrast media can be applied to detect and quantify changes in cancer vessel permeability induced by different inhibitors of angiogenesis; these include bevacizumab, a monoclonal anti-VEGF-antibody (20), celecoxib, a COX-2 inhibitor, and PTK787, a VEGF-receptor tyrosine kinase inhibitor as well as thalidomide (5, 21), all of which can be linked to the VEGF-associated pathways. This study aims at clarifying on the underlying mechanisms for cancer vessel hyperpermeability while further supporting the potential of MMCM-enhanced MRI for the non-invasive evaluation of VEGF expression in individual cancers.…”

“…In published studies using multiple experimental tumors and a prototypic MMCM, albumin-(Gd-DTPA) 35 (4), DCE-MRI has been applied with success to augment the imaging differentiation of benign and malignant tumors ; to grade tumors correspondingly to their microvascular densities (MVD), a surrogate of angiogenesis ; to stratify tumors according to their pathologic aggressiveness defined by pathological Scarff-Bloom-Richardson scoring ; and to detect early cancer responses to multiple forms of angiogenesis inhibiting therapy (5, 6). However, a hypothesized mechanistic link between MRI assayed macromolecular permeability of cancer blood vessels has not been directly supported by demonstration of a positive correlation between MRI-defined macromolecular permeability and immunohistochemical VEGF expression in the same tumors.…”