TY - JOUR
T1 - Chloroquine improves survival and hematopoietic recovery after lethal low-dose-rate radiation
AU - Lim, Yiting
AU - Hedayati, Mohammad
AU - Merchant, Akil A.
AU - Zhang, Yonggang
AU - Yu, Hsiang Hsuan M.
AU - Kastan, Michael B.
AU - Matsui, William
AU - DeWeese, Theodore L.
N1 - Funding Information:
Supported by the American Society of Hematology Scholar Award , American Society for Clinical Oncology Young Investigator Award , American Association for Cancer Research-Astellas USA Fellowship for Basic Cancer Research to A.A.M.; The National Institutes of Health ( R01CA127574, P01CA015396, K23CA107040 ), the Gabrielle’s Angel Foundation for Cancer Research , the Sidney Kimmel Foundation for Cancer Research, and the Goodwin Foundation to (W.M.); The National Institutes of Health ( R01CA71387 and P30CA21765 ), and the American-Lebanese-Syrian Associated Charities of St. Jude Children’s Research Hospital to M.B.K.; and NIH/NCI P50 CA58236 Prostate Cancer SPORE to T.L.D.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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 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). 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.
AB - 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 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). 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.
KW - Ataxia telangiectasia mutated
KW - Ataxia-telangiectasia mutated protein activation
KW - Chloroquine
KW - Hematopoietic progenitor cells
KW - Low-dose-rate radiation
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U2 - 10.1016/j.ijrobp.2012.01.026
DO - 10.1016/j.ijrobp.2012.01.026
M3 - Article
C2 - 22445004
AN - SCOPUS:84866742629
SN - 0360-3016
VL - 84
SP - 800
EP - 806
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 3
ER -