title: High-throughput screening identifies two classes of antibiotics as radioprotectors: tetracyclines and fluoroquinolones.
abstract: OBJECTIVE
  Discovery of agents that protect or mitigate normal tissue from radiation injury during radiotherapy, accidents, or terrorist attacks is of importance. Specifically, bone marrow insufficiency, with possible infection due to immunosuppression, can occur after total body irradiation (TBI) or regional irradiation and is a major component of the acute radiation syndrome. The purpose of this study was to identify novel radioprotectors and mitigators of the hematopoietic system.
  
  
  METHODS
  High-throughput screening of small-molecule libraries was done using viability of a murine lymphocyte line as a readout with further validation in human lymphoblastoid cells. The selected compounds were then tested for their ability to counter TBI lethality in mice.
  
  
  RESULTS
  All of two major classes of antibiotics, tetracyclines and fluoroquinolones, which share a common planar ring moiety, were radioprotective. Furthermore, tetracycline protected murine hematopoietic stem/progenitor cell populations from radiation damage and allowed 87.5% of mice to survive when given before and 35% when given 24 h after lethal TBI. Interestingly, tetracycline did not alter the radiosensitivity of Lewis lung cancer cells. Tetracycline and ciprofloxacine also protected human lymphoblastoid cells, reducing radiation-induced DNA double-strand breaks by 33% and 21%, respectively. The effects of these agents on radiation lethality are not due to the classic mechanism of free radical scavenging but potentially through activation of the Tip60 histone acetyltransferase and altered chromatin structure.
  
  
  CONCLUSIONS
  Tetracyclines and fluoroquinolones can be robust radioprotectors and mitigators of the hematopoietic system with potential utility in anticancer radiotherapy and radiation emergencies.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90095-1714, USA.
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Kim
authors.forename: Julianne M
authors.initials: JM
authors.lastname: Pollard
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Norris
authors.forename: J Tyson
authors.initials: JT
authors.lastname: McDonald
authors.forename: Yingli
authors.initials: Y
authors.lastname: Sun
authors.forename: Ewa
authors.initials: E
authors.lastname: Micewicz
authors.forename: Kelly
authors.initials: K
authors.lastname: Pettijohn
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.forename: Keisuke S
authors.initials: KS
authors.lastname: Iwamoto
authors.forename: James W
authors.initials: JW
authors.lastname: Sayre
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Price
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
authors.forename: William H
authors.initials: WH
authors.lastname: McBride
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology; D018827:Carcinoma, Lewis Lung / Q000628:therapy; D002470:Cell Survival; D004353:Drug Evaluation, Preclinical; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013754:Tetracyclines / Q000494:pharmacology*; D013997:Time Factors; D014916:Whole-Body Irradiation
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D007166:Immunosuppressive Agents; D011837:Radiation-Protective Agents; D013754:Tetracyclines