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Title: Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation

Abstract

Purpose: 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 and Materials: 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 {mu}g 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 micemore » (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). Conclusion: 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.« less

Authors:
 [1]; ; ; ;  [2];  [3];  [4];  [1];  [2]
  1. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)
  2. Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)
  3. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
22149601
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 84; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BONE MARROW CELLS; DOSE RATES; DRUGS; FLUORESCENCE; IN VITRO; IN VIVO; INTRAPERITONEAL INJECTION; IRRADIATION; LETHAL DOSES; MICE; PROTEINS; RADIATION INJURIES; TIBIA

Citation Formats

Lim Yiting, Hedayati, Mohammad, Merchant, Akil A., Zhang Yonggang, Yu, Hsiang-Hsuan M., Kastan, Michael B., Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, Matsui, William, E-mail: matsuwi@jhmi.edu, and DeWeese, Theodore L., E-mail: deweete@jhmi.edu. Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation. United States: N. p., 2012. Web. doi:10.1016/J.IJROBP.2012.01.026.
Lim Yiting, Hedayati, Mohammad, Merchant, Akil A., Zhang Yonggang, Yu, Hsiang-Hsuan M., Kastan, Michael B., Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, Matsui, William, E-mail: matsuwi@jhmi.edu, & DeWeese, Theodore L., E-mail: deweete@jhmi.edu. Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation. United States. doi:10.1016/J.IJROBP.2012.01.026.
Lim Yiting, Hedayati, Mohammad, Merchant, Akil A., Zhang Yonggang, Yu, Hsiang-Hsuan M., Kastan, Michael B., Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, Matsui, William, E-mail: matsuwi@jhmi.edu, and DeWeese, Theodore L., E-mail: deweete@jhmi.edu. Thu . "Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation". United States. doi:10.1016/J.IJROBP.2012.01.026.
@article{osti_22149601,
title = {Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation},
author = {Lim Yiting and Hedayati, Mohammad and Merchant, Akil A. and Zhang Yonggang and Yu, Hsiang-Hsuan M. and Kastan, Michael B. and Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina and Matsui, William, E-mail: matsuwi@jhmi.edu and DeWeese, Theodore L., E-mail: deweete@jhmi.edu},
abstractNote = {Purpose: 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 and Materials: 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 {mu}g 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). Conclusion: 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.},
doi = {10.1016/J.IJROBP.2012.01.026},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 3,
volume = 84,
place = {United States},
year = {2012},
month = {11}
}