Reducing radiation - induced gastrointestinal toxicity — the role of the PHD / HIF axis

Introduction Approximately half of cancer patients will receive radiotherapy with either curative or palliative intent (1). Despite recent advances in radiotherapy treatment planning, normal tissue toxicity still limits the radiation dose that can be safely delivered (1). For example, when radiotherapy treatment is used to treat bladder or prostate cancer, it is often difficult to spare areas of the gastrointestinal (GI) tract, resulting in radiation-induced GI toxicity. Furthermore, patients with abdominal or head and neck tumors have a reasonable prognosis following treatment, making delayed toxic side effects a problem for a significant proportion of long-term survivors (2, 3). Radiation results in detrimental cellular effects either through direct interaction of radiation with DNA or indirectly through the interaction of radiation with water and other tissue components. Indirect radiation effects result in the production of free radicals such as hydroxyl (HO•) and alkoxy (RO2•) radicals as well as reactive nitrogen species (4). Free radicals can react with DNA, resulting in DNA damage. Direct or indirect damage to DNA in the form of DNA breaks or replication stress results in the mounting of a DNA damage response (DDR), which includes p53 activation and cell cycle arrest, senescence, or apoptosis (5–9). A schematic of the sequence of events occurring following irradiation is shown in Figure 1. The effects of radiation-induced normal tissue toxicity vary depending on the type of tissue being irradiated, the volume of tissue receiving irradiation, and the dose and dose rate delivered (3). Toxicity can result in symptoms ranging from mild or moderate to life threatening. In the most severe cases, symptoms may call for supportive treatment or changes to the radiotherapy treatment. Toxic effects are classified as acute, developing within days or weeks of radiation exposure, or as chronic, developing months or years after treatment (1, 2). The majority of patients receiving radiation for the treatment of pelvic or intra-abdominal tumors experience acute radiation-induced GI toxicity symptoms (10). Furthermore, clinical and preclinical studies have shown that acute and chronic radiation-induced GI effects are not separate events, but are in fact linked, with some acute events playing a role in the development of late events (11–15). Late radiation-induced toxicity to the GI tract occurs from at least three months to several months or years after irradiation. Most intestinal compartments are affected by late radiation-induced effects, but damage to vascular and connective tissues is critical to this response (16). Chronic ulceration of the mucosa, mucosal atrophy, and fibrosis can underlie the induction of late toxicity effects. These events can lead to malabsorption, motility problems, and intestinal obstruction or perforation. Dysmotility can be especially problematic if it significantly alters the gut microbiome by increasing bacterial growth, resulting in further malabsorption and diarrhea (17, 18). Complications from radiation can result in the need for surgery or prolonged parenteral nutrition, which can have a negative effect on prognosis (19, 20). Additionally, a fatal syndrome (GI syndrome) involving diarrhea, bacterial translocation, and hemorrhage occurs when large areas of the intestine are irradiated (21). Thus, radiation has both shortand long-term effects that determine patient outcomes after treatment. The effects of radiation-induced damage are complex since the GI tract, while lined with epithelial cells, also contains microvascular and nerve networks, as well as a variety of stromal and immune cells. The pathophysiology of radiation-induced toxicity reflects this complexity (3). Ideal pharmacological agents aimed at reducing radiation-induced toxicity should modulate the toxic effects of radiation on those cellular compartments. If these agents are to be used therapeutically in oncology, they should also be selective towards protection of sensitive normal tissue, but not the tumor. These agents should also allow feasible administration regimes and display a low-toxicity profile. Mitigators, administered after radiotherapy, can also be used in the event of accidental or other types of nonmedical exposures. Mitigators might be Radiotherapy is an effective treatment strategy for cancer, but a significant proportion of patients experience radiationinduced toxicity due to damage to normal tissue in the irradiation field. The use of chemical or biological approaches aimed at reducing or preventing normal tissue toxicity induced by radiotherapy is a long-held goal. Hypoxia-inducible factors (HIFs) regulate the production of factors that may protect several cellular compartments affected by radiation-induced toxicity. Pharmacological inhibitors of prolyl hydroxylase domain–containing enzymes (PHDs), which result in stabilization of HIFs, have recently been proposed as a new class of radioprotectors. In this review, radiation-induced toxicity in the gastrointestinal (GI) tract and the main cellular compartments studied in this context will be discussed. The effects of PHD inhibition on GI radioprotection will be described in detail. Reducing radiation-induced gastrointestinal toxicity — the role of the PHD/HIF axis