Radioprotection

Abstract

Over 40% of cancer patients will require radiation therapy during management of their disease. Although radiation therapy improves the survival of a significant number of cancer patients, both acute radiation toxicity (which manifests during a course of clinical radiotherapy or shortly thereafter), and late toxicity (developing months to years after completion of radiotherapy) compromise overall outcomes for successfully treated cancer patients.

Figure 1. Cell, tissue and organ specific pathways of ionizing irradiation toxicity

Subtotal lung irradiation is shown as an example. Single alveolar pneumoncytes from an area within lung tissue are shown relative to total lung irradiation. Individual cells experience ionizing irradiation-induced production of radical oxygen species (ROS) including superoxide, hydroxyl radical, nitric oxide and peroxynitrite from the interaction of ionizing irradiation with oxygen and water. ROS interaction with pyrimidine and purine bases nuclear DNA produces single and double strand breaks, initiation of DNA repair, communication of DNA damage through the cell cytoplasm to the mitochondrial membrane via (stress activated protein (SAP) kinases) and then translation of pro-apoptotic, BCL2 family members from nucleus to mitochondria.(86) Then follows mitochondrial membrane permeability, cytochrome c disassociation from cardiolipin, and cytoplasmic leakage of cytochrome c which leads to activation of the caspase-3 pathway and apoptosis.(–18, 86) Both dying and irradiated but recovering cells release ROS and inflammatory cytokines including IL-1, TNFα and TGFβ, which directly (through cell to cell contact with other cells in the tissue), and indirectly (via the circulation to cells at distant sites), produce acute local tissue and systemic effects respectively. Within the irradiated tissue differences in radiosensitivity of different cell phenotypes (endothelial cells, alveolar pneumocytes, alveolar macrophages and bronchopulmonary stem cells) contribute to the magnitude of tissue damage. The volume of tissue within the lung that is in the irradiation beam determines as does irradiation dose the magnitude of acute and chronic normal tissue effects.

Figure 2. Organ specific acute and chronic radiation toxicities

Acute tissue toxicity experienced during a radiotherapy treatment course or shortly thereafter is described as symptoms and signs of tissue damage for each organ (left side). Chronic radiation side effects occurring months to years later are also shown (right). Severity and duration of both acute and chronic side effects depends on radiation dose, dose rate, quality of irradiation (greater for high LET radiation beams – See Box 1) and volume of tissue treated.

Figure 3. Targets for development of radioprotector agents based on molecular pathways of the irradiation response

The molecular mechanism of irradiation damage in single cells (effects #1 – 4) and released inflammatory cytokines (effect #5) is defined by several target points where efforts for development of radioprotector drugs can focus. Radioprotectors could target the DNA damage step(–122): (1); molecular translation of the DNA damage event to the mitochondria through the cytoplasm, (2); mitochondrial stabilization by preventing membrane permeability and leakage of cytochrome c, (3); activation of caspases to cause apoptosis(123), (4); or intracellular communication of cellular and tissue damage by elaboration of cytokines, (5). Examples of radioprotector drugs currently under development or in clinical trial are correlated to each irradiation effect and are shown in Table I.