Trastuzumab improves tumor perfusion and vascular delivery of cytotoxic therapy in a murine model of HER2+ breast cancer: preliminary results

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• 作者：Anna G. Sorace ; C. Chad Quarles…
• 关键词：MRI ; Immunohistochemistry ; Normalization ; Angiogenesis ; Herceptin ; Adriamycin ; BT474
• 刊名：Breast Cancer Research and Treatment
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：155
• 期：2
• 页码：273-284
• 全文大小：2,882 KB
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• 作者单位：Anna G. Sorace (1) (2)
  C. Chad Quarles (3)
  Jennifer G. Whisenant (1) (2)
  Ariella B. Hanker (4)
  J. Oliver McIntyre (1) (2) (4)
  Violeta M. Sanchez (6)
  Thomas E. Yankeelov (1) (2) (4) (5) (7) (8)
  
  1. Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA
  2. Vanderbilt Institute of Imaging Science, Vanderbilt University Medical Center, AA-1105 Medical Center North, 1161 21st Ave South, Nashville, TN, 37232-2310, USA
  3. Division of Neuroimaging Research, Barrow Neurological Institute, Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, 85013, USA
  4. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA
  6. Department of Hematology Oncology, Vanderbilt University, Nashville, TN, USA
  5. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
  7. Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
  8. Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  
• 出版者：Springer Netherlands
• ISSN：1573-7217

文摘

To employ in vivo imaging and histological techniques to identify and quantify vascular changes early in the course of treatment with trastuzumab in a murine model of HER2+ breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantitatively characterize vessel perfusion/permeability (via the parameter K trans ) and the extravascular extracellular volume fraction (v _e ) in the BT474 mouse model of HER2+ breast cancer (N = 20) at baseline, day one, and day four following trastuzumab treatment (10 mg/kg). Additional cohorts of mice were used to quantify proliferation (Ki67), microvessel density (CD31), pericyte coverage (α-SMA) by immunohistochemistry (N = 44), and to quantify human VEGF-A expression (N = 29) throughout the course of therapy. Longitudinal assessment of combination doxorubicin ± trastuzumab (N = 42) tested the hypothesis that prior treatment with trastuzumab will increase the efficacy of subsequent doxorubicin therapy. Compared to control tumors, trastuzumab-treated tumors exhibited a significant increase in K trans (P = 0.035) on day four, indicating increased perfusion and/or vessel permeability and a simultaneous significant increase in v _e (P = 0.01), indicating increased cell death. Immunohistochemical and ELISA analyses revealed that by day four the trastuzumab-treated tumors had a significant increase in vessel maturation index (i.e., the ratio of α-SMA to CD31 staining) compared to controls (P < 0.001) and a significant decrease in VEGF-A (P = 0.03). Additionally, trastuzumab dosing prior to doxorubicin improved the overall effectiveness of the therapies (P < 0.001). This study identifies and validates improved perfusion characteristics following trastuzumab therapy, resulting in an improvement in trastuzumab-doxorubicin combination therapy in a murine model of HER2+ breast cancer. This data suggests properties of vessel maturation. In particular, the use of DCE-MRI, a clinically available imaging method, following treatment with trastuzumab may provide an opportunity to optimize the scheduling and improve delivery of subsequent cytotoxic therapy. Keywords MRI Immunohistochemistry Normalization Angiogenesis Herceptin Adriamycin BT474