Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation.
MouseRadiationC57BL/6J and Cdkn1a (p21) knockoutFemalen = Twelve groups of fifteen female C57BL/6 mice for survival;…Oral gavageAZ31 100 mg/kg and/or AZD6738 75 mg/kg, dosing volume 10 mL…2 h prior to total body irradiation
Model: Total body irradiation, 9 or 9.25 Gy delivered in a 137Cs irradiator at 67 cGy/min
ATM inhibition with AZ31 before total body irradiation reduced median time to moribund to 8 days, blocked p21 upregulation and G1 arrest and caused marked intestinal crypt loss, promoting gastrointestinal syndrome. ATR inhibition with AZD6738 did not shorten survival and increased p21 upregulation.
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