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Title: SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation

Abstract

Purpose: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecule indolinone that specifically inhibits this family of kinases. Methods and Materials: Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model. Results: Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation. Conclusions: This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [3];  [4];  [4];  [5]
  1. Vanderbilt University School of Medicine, Nashville, TN (United States)
  2. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States)
  3. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TNUSA (United States)
  4. Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TNUSA (United States)
  5. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TNUSA (United States) and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN (United States). E-mail: dennis.hallahan@vanderbilt.edu
Publication Date:
OSTI Identifier:
20793401
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 64; Journal Issue: 4; Other Information: DOI: 10.1016/j.ijrobp.2005.11.014; PII: S0360-3016(05)02974-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; APOPTOSIS; CAPILLARIES; CARCINOMAS; COMBINED THERAPY; ENDOTHELIUM; FRACTIONATED IRRADIATION; IN VIVO; INHIBITION; IODIDES; IONIZING RADIATIONS; LIMBS; LUNGS; MICE; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RADIOTHERAPY; SKIN; TUBULES; VEINS

Citation Formats

Cuneo, Kyle C., Geng Ling, Tan Jiahuai, Brousal, Jeffrey, Shinohara, Eric T., Osusky, Katherine, Fu, Allie, Shyr, Yu, Wu Huiyun, and Hallahan, Dennis E. SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation. United States: N. p., 2006. Web. doi:10.1016/J.IJROBP.2005.1.
Cuneo, Kyle C., Geng Ling, Tan Jiahuai, Brousal, Jeffrey, Shinohara, Eric T., Osusky, Katherine, Fu, Allie, Shyr, Yu, Wu Huiyun, & Hallahan, Dennis E. SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation. United States. doi:10.1016/J.IJROBP.2005.1.
Cuneo, Kyle C., Geng Ling, Tan Jiahuai, Brousal, Jeffrey, Shinohara, Eric T., Osusky, Katherine, Fu, Allie, Shyr, Yu, Wu Huiyun, and Hallahan, Dennis E. Wed . "SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation". United States. doi:10.1016/J.IJROBP.2005.1.
@article{osti_20793401,
title = {SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation},
author = {Cuneo, Kyle C. and Geng Ling and Tan Jiahuai and Brousal, Jeffrey and Shinohara, Eric T. and Osusky, Katherine and Fu, Allie and Shyr, Yu and Wu Huiyun and Hallahan, Dennis E.},
abstractNote = {Purpose: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecule indolinone that specifically inhibits this family of kinases. Methods and Materials: Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model. Results: Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation. Conclusions: This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.},
doi = {10.1016/J.IJROBP.2005.1},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 4,
volume = 64,
place = {United States},
year = {Wed Mar 15 00:00:00 EST 2006},
month = {Wed Mar 15 00:00:00 EST 2006}
}