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Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium.

Publication ,  Journal Article
Moding, EJ; Lee, C-L; Castle, KD; Oh, P; Mao, L; Zha, S; Min, HD; Ma, Y; Das, S; Kirsch, DG
Published in: J Clin Invest
August 2014

Cells isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation. Kinase inhibitors of ATM, the gene mutated in ataxia telangiectasia, can sensitize tumor cells to radiation therapy, but concern that inhibiting ATM in normal tissues will also increase normal tissue toxicity from radiation has limited their clinical application. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but the role of endothelial cell death in tumor response to radiation therapy remains controversial. Here, we developed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell-specific deletion of Atm to determine whether loss of Atm in endothelial cells sensitizes tumors and normal tissues to radiation. Although deletion of Atm in proliferating tumor endothelial cells enhanced the response of sarcomas to radiation, Atm deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. Blocking cell cycle progression reversed the effect of Atm loss on tumor endothelial cell radiosensitivity. These results indicate that endothelial cells must progress through the cell cycle in order to be radiosensitized by Atm deletion.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

August 2014

Volume

124

Issue

8

Start / End Page

3325 / 3338

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Soft Tissue Neoplasms
  • Sarcoma, Experimental
  • Recombinases
  • Radiation Tolerance
  • Myocardium
  • Mice, Transgenic
  • Mice
  • Immunology
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Moding, E. J., Lee, C.-L., Castle, K. D., Oh, P., Mao, L., Zha, S., … Kirsch, D. G. (2014). Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. J Clin Invest, 124(8), 3325–3338. https://doi.org/10.1172/JCI73932
Moding, Everett J., Chang-Lung Lee, Katherine D. Castle, Patrick Oh, Lan Mao, Shan Zha, Hooney D. Min, Yan Ma, Shiva Das, and David G. Kirsch. “Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium.J Clin Invest 124, no. 8 (August 2014): 3325–38. https://doi.org/10.1172/JCI73932.
Moding EJ, Lee C-L, Castle KD, Oh P, Mao L, Zha S, et al. Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. J Clin Invest. 2014 Aug;124(8):3325–38.
Moding, Everett J., et al. “Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium.J Clin Invest, vol. 124, no. 8, Aug. 2014, pp. 3325–38. Pubmed, doi:10.1172/JCI73932.
Moding EJ, Lee C-L, Castle KD, Oh P, Mao L, Zha S, Min HD, Ma Y, Das S, Kirsch DG. Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. J Clin Invest. 2014 Aug;124(8):3325–3338.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

August 2014

Volume

124

Issue

8

Start / End Page

3325 / 3338

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Soft Tissue Neoplasms
  • Sarcoma, Experimental
  • Recombinases
  • Radiation Tolerance
  • Myocardium
  • Mice, Transgenic
  • Mice
  • Immunology
  • Humans