The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-kappaB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.

/pdf/an-agonist-of-toll-like-receptor-5-has-radioprotective-24x7lybufi.pdf

An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models.

Purpose: The search for ideal protective agents for use in a variety of radiation scenarios has continued for more than six decades. This review evaluates agents and procedures that have the potential to protect against acute and late effects of ionising radiation when administered either before or after radiation exposure.Conclusion: Over the years, extensive experimental studies of radiation-protective agents have enhanced our knowledge of radiation physics, chemistry, and biology. However, translation of agents from animal testing to use in various scenarios, such as prophylactic adjuncts in radiotherapy or post-exposure treatments for potential victims of radiation accidents/incidents, has been slow. Nevertheless, a number of compounds are now available for use in a variety of radiation situations. These include agents approved by the U.S. Food and Drug Administration for use in reducing exposure to internal radionuclides (Prussian blue, calcium diethylenetriamene pentaacetate (DTPA) and zinc DTPA, po...

History and development of radiation-protective agents

Purpose: The increasing global risk of nuclear and radiological accidents or attacks has driven renewed research interest in developing medical countermeasures to potentially injurious exposures to...

https://www.tandfonline.com/doi/pdf/10.1080/09553002.2017.1332438

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures.

World events over the past decade have highlighted the threat of nuclear terrorism as well as an urgent need to develop radiation countermeasures for acute radiation exposures and subsequent bodily injuries. An increased probability of radiological or nuclear incidents due to detonation of nuclear weapons by terrorists, sabotage of nuclear facilities, dispersal and exposure to radioactive materials, and accidents provides the basis for such enhanced radiation exposure risks for civilian populations. Although the search for suitable radiation countermeasures for radiation-associated injuries was initiated more than half a century ago, no safe and effective radiation countermeasure for the most severe of these injuries, namely acute radiation syndrome (ARS), has been approved by the United States Food and Drug Administration (FDA). The dearth of FDA-approved radiation countermeasures has prompted intensified research for a new generation of radiation countermeasures. In this communication, the authors have listed and reviewed the status of radiation countermeasures that are currently available for use, or those that might be used for exceptional nuclear/radiological contingencies, plus a limited few medicines that show early promise but still remain experimental in nature and unauthorized for human use by the FDA.

Medical Countermeasures for Radiation Exposure and Related Injuries: Characterization of Medicines, FDA-Approval Status and Inclusion into the Strategic National Stockpile

Given an ever-increasing risk of nuclear and radiological emergencies, there is a critical need for development of medical radiation countermeasures (MRCs) that are safe, easily administered, and effective in preventing and/or mitigating the potentially lethal tissue damage caused by acute high-dose radiation exposure. Because the efficacy of MRCs for this indication cannot be ethically tested in humans, development of such drugs is guided by the Food and Drug Administration's Animal Efficacy Rule. According to this rule, human efficacious doses can be projected from experimentally established animal efficacious doses based on the equivalence of the drug's effects on efficacy biomarkers in the respective species. Therefore, identification of efficacy biomarkers is critically important for drug development under the Animal Efficacy Rule. CBLB502 is a truncated derivative of the Salmonella flagellin protein that acts by triggering Toll-like receptor 5 (TLR5) signaling and is currently under development as a MRC. Here, we report identification of two cytokines, granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), as candidate biomarkers of CBLB502's radioprotective/mitigative efficacy. Induction of both G-CSF and IL-6 by CBLB502 1) is strictly TLR5-dependent, 2) occurs in a CBLB502 dose-dependent manner within its efficacious dose range in both nonirradiated and irradiated mammals, including nonhuman primates, and 3) is critically important for the ability of CBLB502 to rescue irradiated animals from death. After evaluation of CBLB502 effects on G-CSF and IL-6 levels in humans, these biomarkers will be useful for accurate prediction of human efficacious CBLB502 doses, a key step in the development of this prospective radiation countermeasure.

https://jpet.aspetjournals.org/content/jpet/early/2012/07/26/jpet.112.196071.full.pdf

Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure

5-androstenediol improves survival in clinically unsupported rhesus monkeys with radiation-induced myelosuppression.

HE2100 (androst-5-ene-3β, 17β-diol), an Adrenal Hormone, Protects Rhesus Macaques from Lethal Total Body Irradiation (TBI)- Induced Severe Neutropenia and Thrombocytopenia.

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5-androstenediol improves survival in clinically unsupported rhesus monkeys with radiation-induced myelosuppression.

HE2100 (androst-5-ene-3β, 17β-diol), an Adrenal Hormone, Protects Rhesus Macaques from Lethal Total Body Irradiation (TBI)- Induced Severe Neutropenia and Thrombocytopenia.