Purpose:To test magnetic resonance (MR) contrast media of different molecular weights (MWs) for their potential to characterize noninvasively microvascular changes in an experimental tumor treatment model. Materials and Methods:MD-MBA-435, a poorly differentiated human breast cancer cell line, was implanted into 31 female homozygous athymic rats. Animals were assigned randomly to a control (saline) or drug treatment (monoclonal antibody vascular endothelial growth factor (Mab-VEGF) antibody) group. In both groups, dynamic MR imaging (MRI) was performed in each animal using up to three different contrast media on sequential days at baseline and follow-up examination. The MWs of the contrast media used ranged from 557 Da to 92 kDa. Using a bidirectional kinetic model, tumor microvessel characteristics, including the fractional plasma volume (fPV) and transendothelial permeability (K PS ), were estimated for each contrast medium. These microvascular characteristics were compared between drug and control groups and between contrast media of different MWs.Results: Tumors grew significantly slower (P Ͻ 0.0005) in the drug treatment group than in the control group. Mean K PS and fPV values decreased significantly (P Ͻ 0.05) in the Mab-VEGF antibody-treated group compared to baseline values using intermediate or macromolecular contrast media (MMCM), but did not change significantly using small molecular contrast media (SMCM). In the control groups, mean K PS and mean fPV values did not reach statistical significance for any of the contrast media used. Conclusion:Therapeutic effects of a Mab-VEGF antibody on tumor microvessel characteristics can be monitored by dynamic MRI. Intermediate-size agents, such as Gadomer-17, offer a substantial dynamic range and are less limited by imaging precision and therefore should be considered a practical alternative to monitor antiangiogenesis treatment effects in a clinical setting.

Purpose:To evaluate the diagnostic and prognostic potential of a new protein-binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy. Materials and Methods:Dynamic contrast-enhanced MRI (DCE-MRI) was performed in an experimental cancer model with the use of the novel protein-binding agent B22956/1, a low molecular contrast agent (ProHance™), and a macromolecular contrast medium, albumin-(Gd-DTPA). MDA-MB-435, a human cancer cell line, was implanted in 22 athymic rats. Animals were assigned randomly to a control (saline) or drug-treated (Avastin™) group. MRI was performed at baseline and after nine days of treatment. The transendothelial permeability (K PS ) and the fractional blood volume (fBV) were estimated from the kinetic analysis of dynamic MR data using a two-compartment model. Tumor growth was also measured from volumetric MRI.Results: Tumors grew more slowly, although not significantly (P ϭ 0.07), in the drug-treated group. The K PS determined for B22956/1 decreased significantly in the drugtreated group compared to baseline (P Ͻ 0.05), and progressed significantly in the control group. However, no significant changes were resolved with the use of ProHance or albumin-(Gd-DTPA). Conclusion:With the use of appropriate contrast media, the therapeutic effects of an anti-VEGF antibody on tumor microvessels can be monitored by dynamic MRI. The dynamic range of permeability to B22956/1, and the sensitivity to change of this parameter suggest a potential application in the clinical setting.

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The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (approximately 30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (K(PS)) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (P<0.05) in size and in microvascular permeability (K(PS)) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (P<0.05) in rats treated with PTK787/ZK 222584 and K(PS) values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (P<0.05) in the control than in the drug-treated group. MRI measurements of tumor microvascular response, particularly transendothelial permeability (K(PS)), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy.

The diagnostic potential of a new rapid clearance blood pool contrast medium (P792; MW ‫؍‬ 6.47 kDa) for the MR assessment of microvessel characteristics was assessed in 42 chemicallyinduced breast tumors, with comparisons to albumin-(Gd-DTPA). Microvessel characteristics, including the transendothelial permeability (K PS ) and the fractional blood volume (fPV), were estimated by using dynamic MR data fit to a bidirectional twocompartment model. The MR-derived estimates for K PS and fPV using each contrast agent were compared, and assays using each contrast agent were correlated to the histologic tumor grade (SBR score) and the microvascular density (MVD) counts. Using P792-enhanced data, neither K PS nor fPV showed a statistically significant correlation with the tumor grade or the MVD (P > .05). Conversely, using albumin-(GdDTPA) 30