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Title: Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation

Abstract

Purpose: To investigate the effect of a metronomic (low-dose, high-frequency) small-molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and Materials: Primary human dermal microvascular endothelial cells were exposed to ionizing radiation and/or TW-37 and colony formation, as well as capillary sprouting in three-dimensional collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by cotransplantation of human squamous cell carcinoma cells (OSCC3) and human dermal microvascular endothelial cells seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results: Low-dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low-dose TW-37 or radiation partially inhibited endothelial cell sprout formation, and in combination, these therapies abrogated new sprouting. Combination of metronomic TW-37 and low-dose radiation inhibited tumor growth and resulted in significant increase in time to failure compared with controls, whereas single agents did not. Notably, histopathologic analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions: These resultsmore » demonstrate that metronomic TW-37 potentiates the antitumor effects of radiotherapy and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.« less

Authors:
 [1];  [2]; ; ;  [1];  [3];  [2];  [1];  [4];  [4]
  1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI (United States)
  2. Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI (United States)
  3. Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
21438021
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 78; Journal Issue: 3; Other Information: DOI: 10.1016/j.ijrobp.2010.04.024; PII: S0360-3016(10)00600-0; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANGIOGENESIS; COLONY FORMATION; HEAD; MICE; NECK; RADIATION DOSES; RADIOTHERAPY; ANIMALS; BODY; DOSES; MAMMALS; MEDICINE; NUCLEAR MEDICINE; RADIOLOGY; RODENTS; THERAPY; VERTEBRATES

Citation Formats

Zeitlin, Benjamin D., Spalding, Aaron C., Campos, Marcia S., Ashimori, Naoki, Dong Zhihong, Wang Shaomeng, Lawrence, Theodore S., Noer, Jacques E., E-mail: jenor@umich.ed, Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, and Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI. Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation. United States: N. p., 2010. Web. doi:10.1016/j.ijrobp.2010.04.024.
Zeitlin, Benjamin D., Spalding, Aaron C., Campos, Marcia S., Ashimori, Naoki, Dong Zhihong, Wang Shaomeng, Lawrence, Theodore S., Noer, Jacques E., E-mail: jenor@umich.ed, Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, & Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI. Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation. United States. doi:10.1016/j.ijrobp.2010.04.024.
Zeitlin, Benjamin D., Spalding, Aaron C., Campos, Marcia S., Ashimori, Naoki, Dong Zhihong, Wang Shaomeng, Lawrence, Theodore S., Noer, Jacques E., E-mail: jenor@umich.ed, Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, and Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI. 2010. "Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation". United States. doi:10.1016/j.ijrobp.2010.04.024.
@article{osti_21438021,
title = {Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation},
author = {Zeitlin, Benjamin D. and Spalding, Aaron C. and Campos, Marcia S. and Ashimori, Naoki and Dong Zhihong and Wang Shaomeng and Lawrence, Theodore S. and Noer, Jacques E., E-mail: jenor@umich.ed and Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI and Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI},
abstractNote = {Purpose: To investigate the effect of a metronomic (low-dose, high-frequency) small-molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and Materials: Primary human dermal microvascular endothelial cells were exposed to ionizing radiation and/or TW-37 and colony formation, as well as capillary sprouting in three-dimensional collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by cotransplantation of human squamous cell carcinoma cells (OSCC3) and human dermal microvascular endothelial cells seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results: Low-dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low-dose TW-37 or radiation partially inhibited endothelial cell sprout formation, and in combination, these therapies abrogated new sprouting. Combination of metronomic TW-37 and low-dose radiation inhibited tumor growth and resulted in significant increase in time to failure compared with controls, whereas single agents did not. Notably, histopathologic analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions: These results demonstrate that metronomic TW-37 potentiates the antitumor effects of radiotherapy and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.},
doi = {10.1016/j.ijrobp.2010.04.024},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 3,
volume = 78,
place = {United States},
year = 2010,
month =
}
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