title: Chloroquine improves survival and hematopoietic recovery after lethal low-dose-rate radiation.
abstract: OBJECTIVE
  We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo.
  
  
  METHODS
  C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 μg per 17 g of body weight, 24 hours and 4 hours before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells.
  
  
  RESULTS
  Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015).
  
  
  CONCLUSIONS
  Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection against the harmful effects of LDR radiation.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Lim
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hedayati
authors.forename: Akil A
authors.initials: AA
authors.lastname: Merchant
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hsiang-Hsuan M
authors.initials: HH
authors.lastname: Yu
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Theodore L
authors.initials: TL
authors.lastname: Deweese
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001854:Bone Marrow Cells / Q000528:radiation effects*; D016026:Bone Marrow Transplantation / Q000379:methods; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011828:Radiation Chimera; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000401:mortality; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011837:Radiation-Protective Agents; D025521:Tumor Suppressor Proteins; D002738:Chloroquine; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases