Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy.

While the clonogenic cell killing induced by treatment with 2 Gy IR was further enhanced by treatment with the relevant concentrations of an ATM or ATR inhibitor (KU55933, 2.3-fold at 10 μM [ P = 0.04]; VE-821, 1.6-fold at 1 μM [ P = 0.02]), the potential radio-enhancement observed with the PARP inhibitor did not quite reach statistical significance (1.4-fold at 1 μM [ P = 0.08]).

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The ability of NU5455 to enhance radiation-induced clonogenic survival was highly dependent on incubation time; LD 80 values indicated 1 hour of NU5455 treatment to produce only a marginal effect that did not reach statistical significance (1.2-fold, P = 0.09), 4- to 6-hour treatment to enhance the radiation response significantly (1.5- to 1.7-fold, P < 0.002), and 24-hour treatment to elicit further radio-enhancement (2.4-fold, P <0.0001) ( Figure 2D ).

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