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Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium
Everett J. Moding, … , Shiva Das, David G. Kirsch
Everett J. Moding, … , Shiva Das, David G. Kirsch
Published July 18, 2014
Citation Information: J Clin Invest. 2014;124(8):3325-3338. https://doi.org/10.1172/JCI73932.
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Research Article Article has an altmetric score of 11

Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium

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Abstract

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.

Authors

Everett J. Moding, Chang-Lung Lee, Katherine D. Castle, Patrick Oh, Lan Mao, Shan Zha, Hooney D. Min, Yan Ma, Shiva Das, David G. Kirsch

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Figure 4

Deletion of Atm in p53 WT endothelial cells does not sensitize mice to radiation-induced myocardial necrosis.

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Deletion of Atm in p53 WT endothelial cells does not sensitize mice to r...
(A) Kaplan-Meier plots of myocardial necrosis–free survival for VAtmfl/+, VAtmfl/fl, VPfl/flAtmfl/+, and VPfl/flAtmfl/fl mice after 12 Gy whole-heart irradiation. (B) Kaplan-Meier plots of myocardial necrosis–free survival for VAtmfl/+, VAtmfl/fl, VPfl/flAtmfl/+, and VPfl/flAtmfl/fl mice after whole-heart irradiation with 10 daily fractions of 3 Gy. 1 VPfl/flAtmfl/fl mouse died prior to finishing irradiation and was censored. (C) Kaplan-Meier plots of myocardial necrosis–free survival for VPfl/flAtmfl/+ and VPfl/flAtmfl/fl mice after 8 Gy whole-heart irradiation. Mice of both genotypes were censored due to development of thymic lymphomas prior to heart disease. (D–I) Representative sections of the myocardium of (D–F) a VAtmfl/fl mouse 469 days after whole-heart irradiation and of (G–I) a VPfl/flAtmfl/+ mouse 56 days after whole-heart irradiation, subjected to staining with H&E (D and G) or Masson trichrome (E and H) or immunofluorescence for WGA, TUNEL, and GS-IB4 (F and I). *P < 0.05. Scale bars: 100 μm (D–I).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
Referenced in 1 clinical guideline sources
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