title: Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium.
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.forename: Everett J
authors.initials: EJ
authors.lastname: Moding
authors.forename: Chang-Lung
authors.initials: CL
authors.lastname: Lee
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Castle
authors.forename: Patrick
authors.initials: P
authors.lastname: Oh
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
authors.forename: Hooney D
authors.initials: HD
authors.lastname: Min
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Shiva
authors.initials: S
authors.lastname: Das
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D042783:Endothelial Cells / Q000473:pathology / Q000528:radiation effects; D017353:Gene Deletion; D006321:Heart / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics* / Q000502:physiology*; D045522:Recombinases; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D059016:Tumor Microenvironment / Q000235:genetics / Q000528:radiation effects
chemical_list: D045522:Recombinases; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse