| Abstract: |
Ionization radiation induces DNA damage, most importantly the double-strand DNA break which is difficult to repair and may be lethal to the cell. The sensitivity of cancer cells to radiation is dependent on many factors including capacity to detect and repair DNA damage (termed the DNA-damage response), tumor hypoxia, cell cycle distribution, and radiation dose and fractionation. Inherited deficiencies in the DNA-damage response are associated with profound cancer predispositions, reflecting the essential role of DNA repair on organismal function. Radiosensitizing drugs improve the efficacy of radiation therapy. For example, the addition of temozolomide to radiation therapy for glioblastoma patients with O-6-methylguanine-DNA methyltransferase (MGMT) epigenetic silencing improves survival compared to radiation therapy alone. Early toxicity following radiation therapy is reversible and occurs due to depletion of cells in highly proliferative tissues, while late toxicity is permanent and occurs due to fibrosis and loss of organ function. Ionizing radiation can cause genomic instability and acquisition of a mutator phenotype through damage to genes critical for DNA repair, making cells less likely to repair additional oncogenic mutations. As a result, radiation therapy is associated with risk of secondary malignancy. Radiation therapy most commonly utilizes photons, which are high-energy X-rays. Photons collide with orbital electrons to produce reactive oxygen species which are highly volatile and damage nearby DNA. Proton radiation therapy utilizes hydrogen atoms stripped of their electrons. Compared to photons, the depth-dose characteristics of protons allow for decreased radiation dose to normal tissues adjacent to the tumor. As a result, protons offer the potential to reduce early and late toxicity, including risk of secondary malignancy. © Springer Nature Switzerland AG 2020. |
