Radiotherapy (RT) results in the production of a variety of ionizing radiation-induced lesion in DNA. Specific pathways of DNA repair are required to repair the variety of lesions, which include DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), DNA base alterations, and DNA-DNA or DNA-protein cross-links. Nonrepaired DNA damage can lead to normal and tumor cell death via apoptosis, mitotic catastrophe, autophagy, or terminal growth arrest senescence. Targeting the sensing and repair of DNA damage is an exciting concept. This must be combined with precision RT to limit the volume of irradiated normal tissue, including the use of image-guided radiotherapy (IGRT) and brachytherapy. The therapeutic ratio of combined targeting of DNA combined with RT could also be preserved using biological approaches and includes the following: (1) the documentation of relative defects in DNA damage sensing and repair in malignant cells; (2) the preferential use of certain DNA repair pathways (eg, base excision repair or homologous recombination) in malignant tissues compare with normal tissues; (3) the targeting of repair defects in chronically hypoxic cells; and (4) optimal scheduling of a DNA repair inhibitor in the neoadjuvant, concurrent, or adjuvant combined treatment settings. In this review, we discuss the general rationale and the optimal timing and duration of DNA repair inhibition during fractionated RT with the emphasis on preserving the therapeutic ratio of cancer treatment.
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