| Antiangiogenic cancer therapy: monitoring with molecular US and a clinically translatable contrast agent (BR55). | |
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MedLine Citation:
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PMID: 20515975 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: To develop and test human kinase insert domain receptor (KDR)-targeted microbubbles (MBs) (MB(KDR)) for imaging KDR at the molecular level and for monitoring antiangiogenic therapy in a human colon cancer xenograft tumor model in mice. MATERIALS AND METHODS: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. A heterodimeric peptide that binds to human KDR with low nanomolar affinity (K(D) = 0.5 nmol/L) was coupled onto the surface of perfluorobutane-containing lipid-shelled MBs (MB(KDR)). Binding specificity of MB(KDR) to human KDR and cross-reactivity with murine vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) were tested in cell culture under flow shear stress conditions (at 100 sec(-1)). In vivo binding specificity of MB(KDR) to VEGFR2 was tested in human LS174T colon cancer xenografts in mice with a 40-MHz ultrasonographic (US) transducer. Targeted contrast material-enhanced US imaging signal by using MB(KDR) was longitudinally measured during 6 days in tumors with (n = 6) and without (n = 6) antiangiogenic treatment (anti-VEGF antibody). Ex vivo VEGFR2 staining and microvessel density analysis were performed. Significant differences were evaluated (t, Mann-Whitney, or Wilcoxon test). RESULTS: Cell culture experiments showed four times greater binding specificity of MB(KDR) to human KDR and cross-reactivity to murine VEGFR2 (P < or = .01). In vivo imaging signal was more than three times higher (P = .01) with MB(KDR) compared with control MBs and decreased significantly (approximately fourfold lower, P = .03) following in vivo receptor blocking with anti-VEGFR2 antibody. One day after initiation of antiangiogenic therapy, imaging signal was significantly decreased (approximately 46% lower, P = .02) in treated versus untreated tumors; it remained significantly lower (range, 46%-84% decreased; P = .038) during the following 5 days. Microvessel density was significantly reduced (P = .04) in treated (mean, 7.3 microvessels per square millimeter +/- 4.7 [standard deviation]) versus untreated tumors (mean, 22.0 microvessels per square millimeter +/- 9.4); VEGFR2 expression was significantly decreased (>50% lower, P = .03) in treated tumors. CONCLUSION: Human MB(KDR) allow in vivo imaging and longitudinal monitoring of VEGFR2 expression in human colon cancer xenografts. |
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Authors:
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Marybeth A Pysz; Kira Foygel; Jarrett Rosenberg; Sanjiv S Gambhir; Michel Schneider; Jürgen K Willmann |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-06-01 |
Journal Detail:
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Title: Radiology Volume: 256 ISSN: 1527-1315 ISO Abbreviation: Radiology Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-26 Completed Date: 2010-09-24 Revised Date: 2011-08-03 |
Medline Journal Info:
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Nlm Unique ID: 0401260 Medline TA: Radiology Country: United States |
Other Details:
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Languages: eng Pagination: 519-27 Citation Subset: AIM; IM |
Affiliation:
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Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307, Stanford, CA 94305, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Angiogenesis Inhibitors
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administration & dosage* Animals Cell Line, Tumor Colonic Neoplasms / drug therapy*, ultrasonography* Contrast Media Drug Delivery Systems / methods Humans Mice Microbubbles Molecular Probe Techniques* Peptides / diagnostic use* Reproducibility of Results Sensitivity and Specificity Ultrasonography / methods* |
| Grant Support | |
ID/Acronym/Agency:
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CA114747 P50/CA/NCI NIH HHS; R21 CA139279/CA/NCI NIH HHS; R21 CA139279-01A1/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Angiogenesis Inhibitors; 0/Contrast Media; 0/Peptides |
| Comments/Corrections | |
Comment In:
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Radiology. 2010 Aug;256(2):331-3
[PMID:
20656826
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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