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Page 245 Nickoloff et al. Cancer Drug Resist 2021;4:244-63 I http://dx.doi.org/10.20517/cdr.2020.89

INTRODUCTION
Ionizing radiation has been used to treat cancer for more than 120 years, and radiotherapy is widely used
to treat many types of cancer. More than half of cancer patients receive radiation as monotherapy or in
combination with surgery, genotoxic chemotherapy, and targeted therapy. Radiation is usually delivered
with external beams, but radioactive implants (brachytherapy) are used to treat prostate, head and neck,
[1]
breast, eye, and other cancers . Regardless of the mode of delivery, ionizing radiation is effective because it
causes cytotoxic DNA damage (i.e., it is genotoxic), and in this way it is similar to genotoxic chemotherapy.
However, radiotherapy is only effective for local tumor control and isolated metastases, whereas genotoxic
chemotherapy, delivered systemically, can also treat widespread metastatic disease. There is evidence that
radiotherapy may be effective against distant disease, through immune-mediated, non-targeted abscopal
[2]
effects, but this approach is currently limited to pre-clinical studies . Radiotherapy has several benefits for
patients: It is non-invasive, painless, and has low rates of severe side-effects, highlighting another difference
from systemic, genotoxic chemotherapy which often causes side effects that compromise patient quality
of life. Although metastatic disease is ultimately responsible for most cancer deaths, the importance of
local tumor control should not be underestimated. As noted in a widely used radiation oncology textbook,
“…for tumors with high metastatic potential, such as breast, prostate, and lung…improved locoregional
[3]
control by radiotherapy with or without chemotherapy enhances overall [patient] survival” . Among
the ongoing challenges in the radiotherapy field are the adverse effects of radiation on sensitive, normal
tissues adjacent to tumors, in particular brain, spinal cord, and heart. In contrast, systemic genotoxins
cause widespread damage, in particular to proliferative normal tissues including gastrointestinal lining and
bone marrow, causing nausea and anemia, as well as non-proliferating brain tissue, causing chemotherapy-
[4]
induced cognitive impairment or “chemo-brain” . For both genotoxic chemotherapeutics and radiation,
there is great interest in understanding mechanisms of intrinsic and acquired tumor cell resistance to these
[5-8]
agents .
The goal of radiotherapy is to completely eradicate tumor cells while sparing nearby normal tissue.
The efficacy of radiotherapy has greatly improved with the development of advanced techniques for
diagnostic imaging, beam-focusing, and beam-shaping [9,10] , and treatment outcomes continue to improve
as combination therapeutic strategies mature . Two ways that combination therapies can improve
[11]
therapeutic gain are to radiosensitize tumor cells, especially those with high intrinsic or acquired
radioresistance, and protect normal tissue. There are many biological parameters that modulate tumor
and normal cell responses to radiation, such as cell type, cell cycle phase, tissue/tumor microenvironment,
oxygen levels, DNA repair capacity, and others. We begin with a synopsis of radiation damage to cellular
components; cellular responses to radiation damage; environmental and cellular factors that determine
normal and tumor cell radiosensitivity; and strategies used to counter tumor radioresistance or protect
normal tissue from radiation damage. We then discuss how DNA repair and DNA damage response (DDR)
pathways can be exploited to radiosensitize tumor cells and protect normal tissue during radiotherapy.

IONIZING RADIATION DAMEGE TO CELLULAR COMPONENTS AND CELL RESPONSES
Genotoxic chemotherapeutics and ionizing radiation kill cells by directly or indirectly damaging DNA
or interfering with DNA metabolism (DNA polymerases, topoisomerases, or chromosome segregation
machinery). Ionizing radiation, whether delivered by X-rays, protons, or carbon ions, causes damage to
cellular components through direct energy absorption or indirectly by ionizing water to generate reactive
[12]
oxygen species (ROS), including hydroxyl radicals, superoxide, and hydrogen peroxide . ROS are highly
reactive and interact almost immediately with cellular components, causing oxidative and other damage to
proteins, nucleic acids, and membrane components. ROS are also generated during normal cell metabolism,
primarily from mitochondrial function [13,14] . Cells survive and thrive despite > 100,000 spontaneous DNA
lesions/cell/day, including ~10,000 single-strand breaks and ~50 DNA double-strand breaks (DSBs) [15-17] .