Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model
| Autor: | Kathryn L Parsons-Reponte, Eduardo E. Mundo, Leslie A. Khawli, Frank-Peter Theil, Nicholas Lewin-Koh, Cinthia V. Pastuskovas, Daniela Bumbaca, Jason Ho, C. Andrew Boswell, Eric Cheng, Jay Tibbitts, Sarajane Ross, Mark X. Sliwkowski, Sheila Bheddah, Sheila Ulufatu, Katherine R. Kozak, Suzanna Clark, Marjie Van Hoy, Nicholas Majidy, Josefa Chuh, Simon Williams, Paul J. Fielder, Tapan K. Nayak, Gary Cain, Peter Nauka |
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| Rok vydání: | 2012 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Biodistribution Bevacizumab Receptor ErbB-2 Antibody Affinity Mice Nude Breast Neoplasms Vascular permeability Pharmacology Antibodies Monoclonal Humanized Multimodal Imaging Iodine Radioisotopes Mice Breast cancer Pharmacokinetics Antibody Specificity Trastuzumab Cell Line Tumor medicine Animals Humans Tissue Distribution skin and connective tissue diseases Dose-Response Relationship Drug business.industry Indium Radioisotopes Antibodies Monoclonal medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Oncology Positron-Emission Tomography Female Tomography X-Ray Computed business Perfusion medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 11:752-762 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Both human epidermal growth factor receptor 2 (HER-2/neu) and VEGF overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-HER2) with bevacizumab (anti-VEGF) has shown promising results in preclinical xenograft studies and in clinical trials. However, despite the known antiangiogenic mechanism of anti-VEGF antibodies, relatively little is known about their effects on the pharmacokinetics and tissue distribution of other antibodies. This study aimed to measure the disposition properties, with a particular emphasis on tumor uptake, of trastuzumab in the presence or absence of anti-VEGF. Radiolabeled trastuzumab was administered alone or in combination with an anti-VEGF antibody to mice bearing HER2-expressing KPL-4 breast cancer xenografts. Biodistribution, autoradiography, and single-photon emission computed tomography–X-ray computed tomography imaging all showed that anti-VEGF administration reduced accumulation of trastuzumab in tumors despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2, showing reduced vascular permeability to macromolecules. Reduced tumor blood flow (P < 0.05) was observed following anti-VEGF treatment, with no significant differences in the other physiologic parameters measured despite immunohistochemical evidence of reduced vascular density. In conclusion, anti-VEGF preadministration decreased tumor uptake of trastuzumab, and this phenomenon was mechanistically attributed to reduced vascular permeability and blood perfusion. These findings may ultimately help inform dosing strategies to achieve improved clinical outcomes. Mol Cancer Ther; 11(3); 752–62. ©2012 AACR. |
| Databáze: | OpenAIRE |
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