Development Of Radioprotectors Research Articles

Effect of adenosine treatment on ionizing radiation toxicity in zebrafish early life stages.

The danger of ionizing radiation exposure to human health is a concern. Since its wide use in medicine and industry, the development of radioprotectors has been very significant. Adenosine exerts anti-inflammatory actions and promotes tissue protection and repair, by activating the P1 receptors (A1, A2A, A2B, and A3). Zebrafish (Danio rerio) is an appropriate tool in the fields of toxicology and pharmacology, including the evaluation of radiobiological outcomes and in the search for radioprotector agents. This study aims to evaluate the effect of adenosine in the toxicity induced by radiation in zebrafish. Embryos were treated with 1, 10, or 100µM adenosine, 30min before the exposure to 15Gy of gamma radiation. Adenosine potentiated the effects of radiation in heart rate, body length, and pericardial edema. We evaluated oxidative stress, tissue remodeling and inflammatory. It was seen that 100µM adenosine reversed the inflammation induced by radiation, and that A2A2 and A2B receptors are involved in these anti-inflammatory effects. Our results indicate that P1R activation could be a promising pharmacological strategy for radioprotection.

PK-PD based optimal dose and time for orally administered supra-pharmacological dose of melatonin to prevent radiation induced mortality in mice

AimsThe study reports preclinical pharmacokinetics (PK) and correlation with pharmacological effect at suprapharmacological dose of orally administered melatonin along with time and dose optimization, which have been lacking in earlier reports of radioprotection using melatonin. MethodsPK of melatonin in C57BL/6 mice was evaluated after dose of 250 mg/kg using HPLC. Tissue distribution study was conducted in vital organs following oral administration. Plasma total antioxidant capacity (TAC) was determined by ABTS+ radical assay and was correlated to plasma concentrations of melatonin. Using the outcomes of PK and Pharmacodynamics (PD), survival study was conducted for optimization of ‘drug radiation gap period’ (DRGP). Optimal oral dose for radioprotection was determined using survival as an end point. Key findingsPK analysis of melatonin revealed Tmax at 5 min with closely spaced another distinct concentration peak at 20 min. Plasma TAC of melatonin showed similar peaks at 5 min and 45 min, with the highest TAC at 45 min. Survival following a lethal (9 Gy) radiation dose was 20% and 40% after 5 and 45 min of melatonin administration, respectively. DRGP for melatonin was thus 45 min, while optimal oral dose ranged from 125 to 250 mg/kg. PK parameters at 250 mg/kg dose were qualitatively similar to low dose of melatonin, thus preventing chances of unexpected toxicity. SignificanceSurvival enhancement at 45 min suggested as probable interval required as ‘DRGP’. The optimum oral therapeutic window appears large with no substantial toxicity. The outcomes will be useful in development of radioprotectors as well as other therapeutic applications.

Development of p53-targeting drugs that increase radioresistance in normal tissues.

Radiation damage to normal tissues is a serious concern in radiation therapy. Advances in radiotherapeutic technology have improved the dose distribution of the target volumes and risk organs, but damage to risk organs that are located within the irradiation field still limits the allowable prescription dose. To overcome this dose-limiting toxicity, and to further improve the efficacy of radiotherapy, the development of drugs that protect normal tissues but not cancer tissues from the effects of radiation are expected to be developed based on molecular target-based drugs. p53 is a well-known transcription factor that is closely associated with radiation-induced cell death. In radiation-injured tissues, p53 induces apoptosis in hematopoietic lineages, whereas it plays a radioprotective role in the gastrointestinal epithelium. These facts suggest that p53 inhibitor would be effective for radioprotection of the hematopoietic system, and that a drug that upregulates the radioprotective functions of p53 would enhance the radioresistance of gastrointestinal tissues. In this review, we summarize recent progress regarding the prevention of radiation injury by regulating p53 and provide new strategic insights into the development of radioprotectors in radiotherapy. J. Med. Invest. 66 : 219-223, August, 2019.

Abstract 1662: Development of a novel mouse model to study image-guided radiation-induced gastrointestinal injury and its application in pre-clinical research

Abstract Radiotherapy is a major treatment modality typically used in conjunction with surgery and/or chemotherapy in treating a variety of cancers. While effective in controlling or eliminating localized tumors or preventing recurrence, radiation does induce a host of normal tissue toxicities. Gastrointestinal (GI) side effects from radiation treatment are very common; often this limits the dose of radiation that can be delivered to GI tumors and thereby its effectiveness. Thus, the discovery and clinical implementation of the use of bowel radioprotectors and mitigators could have significant clinical impact. The purpose of this study was to develop a novel method of inflicting localized radiation-induced GI damage in order to establish a more physiological model of damage and aid the development of radioprotectors. Current models, while useful in elucidating the pathophysiological characteristics of broad field radiation, are hampered by complex surgical procedures (exteriorizing the rat intestine and then irradiating the herniated loop of bowel) which can introduce confounding factors such as infection, inflammation and fibrosis or involve whole abdominal irradiation, recapitulating a pathophysiology that is not relevant to clinical practice. Here we surgically glued a 2mm diameter radiopaque marker made of bismuth subcarbonate onto the surface of the mouse (C57BL/6) jejunum to serve as a target for radiation treatment. One-week post-surgery the mice were imaged with cone-beam CT to locate the marker, and irradiated with 12Gy on the marker using the Small Animal Radiation Research Platform (SARRP®) using a 5×5mm collimator. Mice were sacrificed at various time points post-RT and intestinal tissue directly under, adjacent to, and distal to the marker were collected to assess both morphological and molecular features of radiation-induced damage and inflammation. These included levels of γ-H2AX, multiple cytokines, EdU incorporation, TUNEL assay and intestinal stem cell marker analysis. Our findings suggest that our image-guided radiation injury mouse model is feasible since we observed a high survival rate post-surgery (approx. 90%). DNA damage, cell-cycle arrest, intestinal crypt apoptosis and inflammation were all significantly higher in the irradiated mice and confined to the immediately irradiated or adjacent area. However, IR-induced damage at 12Gy over 5mm appeared to be transient, as we observed regeneration of the majority of crypts at later time points post- IR. We are currently extending these findings with higher doses of radiation in the presence and absence of clinically used radioprotectors such as curcumin. Our model constitutes a new tool to rapidly evaluate multiple biological markers of DNA damage in the mouse intestine and we believe it will be valuable in future screens for radiation response modifiers and the study of molecular aspects of IR damage. Citation Format: Ioannis Verginadis, Rahul Kanade, Edgar Ben-Josef, Constantinos Koumenis. Development of a novel mouse model to study image-guided radiation-induced gastrointestinal injury and its application in pre-clinical research. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1662.

TU‐H‐BRB‐03: The BARDA Chemical/Radiological/Nuclear Countermeasures Effort

The US government has substantial research and development activities underway for medical countermeasures that will insure the long‐term safety and survival of the country's population after unfortunate large‐scale biological, chemical and radiological and nuclear events. Preparedness includes research and development of medical countermeasures to address radiation‐induced cutaneous and internal injury from radiation and nuclear events as well as for minimizing radiation risks incurred during and after travel in space. Other important research and development efforts include the repurposing of countermeasures and development of radioprotectors and mitigators to improve the outcome of radiation treatment. Participating agencies include NIAID, BARDA, NCI, and NASA, with examples of research and development funding that includes the Centers for Medical Countermeasures against Radiation (CMCR) consortia (NIAID) and primary and sub‐contracts with commercial entities (BARDA). Each of these programs requires substantial medical and health physics effort in collaboration with biology colleagues to provide a range of radiation sources, dosimetry instrumentation and assessment methods, and animal models for specific radiation‐induced effects and injuries. Radiation countermeasure activities for government agencies will be reviewed, the importance of model development will be stressed, example radiation countermeasure research projects will be reviewed, and the roles for medical physicists will be discussed. Learning Objectives: Review US national radiation countermeasure activities. Review the roles for medical physicists in radiation countermeasures research and development. Understand specific physics challenges in radiation research that need solutions.Research for JD Bourland supported in part by: NIH/NIAID, U19 AI67798 (subcontract 131714). NIH/NCI, R01CA155293. HHSO10020130019C, BARDA/Argentum Medical LLC.; J. Bourland, Research supported in part by:NIH/NIAID, U19 AI67798 (subcontract 131714); NIH/NCI, R01CA155293; HHSO10020130019C, BARDA/Argentum Medical LLC.; P. Prasanna, Supported by the Radiation Research Program, National Cancer Institute

TU‐H‐BRB‐05: Radiation Countermeasures and the NASA Space Radiation Program

The US government has substantial research and development activities underway for medical countermeasures that will insure the long‐term safety and survival of the country's population after unfortunate large‐scale biological, chemical and radiological and nuclear events. Preparedness includes research and development of medical countermeasures to address radiation‐induced cutaneous and internal injury from radiation and nuclear events as well as for minimizing radiation risks incurred during and after travel in space. Other important research and development efforts include the repurposing of countermeasures and development of radioprotectors and mitigators to improve the outcome of radiation treatment. Participating agencies include NIAID, BARDA, NCI, and NASA, with examples of research and development funding that includes the Centers for Medical Countermeasures against Radiation (CMCR) consortia (NIAID) and primary and sub‐contracts with commercial entities (BARDA). Each of these programs requires substantial medical and health physics effort in collaboration with biology colleagues to provide a range of radiation sources, dosimetry instrumentation and assessment methods, and animal models for specific radiation‐induced effects and injuries. Radiation countermeasure activities for government agencies will be reviewed, the importance of model development will be stressed, example radiation countermeasure research projects will be reviewed, and the roles for medical physicists will be discussed. Learning Objectives: Review US national radiation countermeasure activities. Review the roles for medical physicists in radiation countermeasures research and development. Understand specific physics challenges in radiation research that need solutions.Research for JD Bourland supported in part by: NIH/NIAID, U19 AI67798 (subcontract 131714). NIH/NCI, R01CA155293. HHSO10020130019C, BARDA/Argentum Medical LLC.; J. Bourland, Research supported in part by:NIH/NIAID, U19 AI67798 (subcontract 131714); NIH/NCI, R01CA155293; HHSO10020130019C, BARDA/Argentum Medical LLC.; P. Prasanna, Supported by the Radiation Research Program, National Cancer Institute

TU‐H‐BRB‐02: The NIAID Radiation/Nuclear Medical Countermeasures Program

The US government has substantial research and development activities underway for medical countermeasures that will insure the long‐term safety and survival of the country's population after unfortunate large‐scale biological, chemical and radiological and nuclear events. Preparedness includes research and development of medical countermeasures to address radiation‐induced cutaneous and internal injury from radiation and nuclear events as well as for minimizing radiation risks incurred during and after travel in space. Other important research and development efforts include the repurposing of countermeasures and development of radioprotectors and mitigators to improve the outcome of radiation treatment. Participating agencies include NIAID, BARDA, NCI, and NASA, with examples of research and development funding that includes the Centers for Medical Countermeasures against Radiation (CMCR) consortia (NIAID) and primary and sub‐contracts with commercial entities (BARDA). Each of these programs requires substantial medical and health physics effort in collaboration with biology colleagues to provide a range of radiation sources, dosimetry instrumentation and assessment methods, and animal models for specific radiation‐induced effects and injuries. Radiation countermeasure activities for government agencies will be reviewed, the importance of model development will be stressed, example radiation countermeasure research projects will be reviewed, and the roles for medical physicists will be discussed. Learning Objectives: Review US national radiation countermeasure activities. Review the roles for medical physicists in radiation countermeasures research and development. Understand specific physics challenges in radiation research that need solutions.Research for JD Bourland supported in part by: NIH/NIAID, U19 AI67798 (subcontract 131714). NIH/NCI, R01CA155293. HHSO10020130019C, BARDA/Argentum Medical LLC.; J. Bourland, Research supported in part by:NIH/NIAID, U19 AI67798 (subcontract 131714); NIH/NCI, R01CA155293; HHSO10020130019C, BARDA/Argentum Medical LLC.; P. Prasanna, Supported by the Radiation Research Program, National Cancer Institute

TU‐H‐BRB‐04: Radiation Countermeasures and the NCI Radiation Research Program

The US government has substantial research and development activities underway for medical countermeasures that will insure the long‐term safety and survival of the country's population after unfortunate large‐scale biological, chemical and radiological and nuclear events. Preparedness includes research and development of medical countermeasures to address radiation‐induced cutaneous and internal injury from radiation and nuclear events as well as for minimizing radiation risks incurred during and after travel in space. Other important research and development efforts include the repurposing of countermeasures and development of radioprotectors and mitigators to improve the outcome of radiation treatment. Participating agencies include NIAID, BARDA, NCI, and NASA, with examples of research and development funding that includes the Centers for Medical Countermeasures against Radiation (CMCR) consortia (NIAID) and primary and sub‐contracts with commercial entities (BARDA). Each of these programs requires substantial medical and health physics effort in collaboration with biology colleagues to provide a range of radiation sources, dosimetry instrumentation and assessment methods, and animal models for specific radiation‐induced effects and injuries. Radiation countermeasure activities for government agencies will be reviewed, the importance of model development will be stressed, example radiation countermeasure research projects will be reviewed, and the roles for medical physicists will be discussed. Learning Objectives: Review US national radiation countermeasure activities. Review the roles for medical physicists in radiation countermeasures research and development. Understand specific physics challenges in radiation research that need solutions.Research for JD Bourland supported in part by: NIH/NIAID, U19 AI67798 (subcontract 131714). NIH/NCI, R01CA155293. HHSO10020130019C, BARDA/Argentum Medical LLC.; J. Bourland, Research supported in part by:NIH/NIAID, U19 AI67798 (subcontract 131714); NIH/NCI, R01CA155293; HHSO10020130019C, BARDA/Argentum Medical LLC.; P. Prasanna, Supported by the Radiation Research Program, National Cancer Institute

TU‐H‐BRB‐00: Radiation Countermeasures Research and Development

The US government has substantial research and development activities underway for medical countermeasures that will insure the long‐term safety and survival of the country's population after unfortunate large‐scale biological, chemical and radiological and nuclear events. Preparedness includes research and development of medical countermeasures to address radiation‐induced cutaneous and internal injury from radiation and nuclear events as well as for minimizing radiation risks incurred during and after travel in space. Other important research and development efforts include the repurposing of countermeasures and development of radioprotectors and mitigators to improve the outcome of radiation treatment. Participating agencies include NIAID, BARDA, NCI, and NASA, with examples of research and development funding that includes the Centers for Medical Countermeasures against Radiation (CMCR) consortia (NIAID) and primary and sub‐contracts with commercial entities (BARDA). Each of these programs requires substantial medical and health physics effort in collaboration with biology colleagues to provide a range of radiation sources, dosimetry instrumentation and assessment methods, and animal models for specific radiation‐induced effects and injuries. Radiation countermeasure activities for government agencies will be reviewed, the importance of model development will be stressed, example radiation countermeasure research projects will be reviewed, and the roles for medical physicists will be discussed. Learning Objectives: Review US national radiation countermeasure activities. Review the roles for medical physicists in radiation countermeasures research and development. Understand specific physics challenges in radiation research that need solutions.Research for JD Bourland supported in part by: NIH/NIAID, U19 AI67798 (subcontract 131714). NIH/NCI, R01CA155293. HHSO10020130019C, BARDA/Argentum Medical LLC.; J. Bourland, Research supported in part by:NIH/NIAID, U19 AI67798 (subcontract 131714); NIH/NCI, R01CA155293; HHSO10020130019C, BARDA/Argentum Medical LLC.; P. Prasanna, Supported by the Radiation Research Program, National Cancer Institute

TU‐H‐BRB‐01: Physics and Dosimetry for Radiation Countermeasure Research

The US government has substantial research and development activities underway for medical countermeasures that will insure the long‐term safety and survival of the country's population after unfortunate large‐scale biological, chemical and radiological and nuclear events. Preparedness includes research and development of medical countermeasures to address radiation‐induced cutaneous and internal injury from radiation and nuclear events as well as for minimizing radiation risks incurred during and after travel in space. Other important research and development efforts include the repurposing of countermeasures and development of radioprotectors and mitigators to improve the outcome of radiation treatment. Participating agencies include NIAID, BARDA, NCI, and NASA, with examples of research and development funding that includes the Centers for Medical Countermeasures against Radiation (CMCR) consortia (NIAID) and primary and sub‐contracts with commercial entities (BARDA). Each of these programs requires substantial medical and health physics effort in collaboration with biology colleagues to provide a range of radiation sources, dosimetry instrumentation and assessment methods, and animal models for specific radiation‐induced effects and injuries. Radiation countermeasure activities for government agencies will be reviewed, the importance of model development will be stressed, example radiation countermeasure research projects will be reviewed, and the roles for medical physicists will be discussed. Learning Objectives: Review US national radiation countermeasure activities. Review the roles for medical physicists in radiation countermeasures research and development. Understand specific physics challenges in radiation research that need solutions.Research for JD Bourland supported in part by: NIH/NIAID, U19 AI67798 (subcontract 131714). NIH/NCI, R01CA155293. HHSO10020130019C, BARDA/Argentum Medical LLC.; J. Bourland, Research supported in part by:NIH/NIAID, U19 AI67798 (subcontract 131714); NIH/NCI, R01CA155293; HHSO10020130019C, BARDA/Argentum Medical LLC.; P. Prasanna, Supported by the Radiation Research Program, National Cancer Institute

MnTE-2-PyP reduces prostate cancer growth and metastasis by suppressing p300 activity and p300/HIF-1/CREB binding to the promoter region of the PAI-1 gene

To improve radiation therapy-induced quality of life impairments for prostate cancer patients, the development of radio-protectors is needed. Our previous work has demonstrated that MnTE-2-PyP significantly protects urogenital tissues from radiation-induced damage. So, in order for MnTE-2-PyP to be used clinically as a radio-protector, it is fully necessary to explore the effect of MnTE-2-PyP on human prostate cancer progression. MnTE-2-PyP inhibited prostate cancer growth in the presence and absence of radiation and also inhibited prostate cancer migration and invasion. MnTE-2-PyP altered p300 DNA binding, which resulted in the inhibition of HIF-1β and CREB signaling pathways. Accordingly, we also found that MnTE-2-PyP reduced the expression of three genes regulated by HIF-1β and/or CREB: TGF-β2, FGF-1 and PAI-1. Specifically, MnTE-2-PyP decreased p300 complex binding to a specific HRE motif within the PAI-1 gene promoter region, suppressed H3K9 acetylation, and consequently, repressed PAI-1 expression. Mechanistically, less p300 transcriptional complex binding is not due to the reduction of binding between p300 and HIF-1/CREB transcription factors, but through inhibiting the binding of HIF-1/CREB transcription factors to DNA. Our data provide an in depth mechanism by which MnTE-2-PyP reduces prostate cancer growth and metastasis, which validates the clinical use of MnTE-2-PyP as a radio-protector to enhance treatment outcomes in prostate cancer radiotherapy.

Radioprotective agents for radiation therapy: future trends.

Only two radioprotective compounds, amifostine and palifermin, currently have the US FDA approval for use in radiation therapy. However, several agents have been reported that show therapeutic promise. Many of these agents are free radical scavengers/antioxidants. Superoxide dismutase and superoxide dismutase mimetics, nitroxides and dietary antioxidants are all being investigated. Recently, alternative strategies of drug development have been evolving, which focus on targeting the series of cellular insult recognition/repair responses initiated following radiation. These agents, which include cytokines/growth factors, angiotensin-converting enzyme inhibitors and apoptotic modulators, show promise of having significant impact on the mitigation of radiation injury. Herein, we review current literature on the development of radioprotectors with emphasis on compounds with proven or potential usefulness in radiation therapy.

Radioprotective role of clinical drug diclofenac sodium

The potential of clinical drug diclofenac sodium which is routinely used in clinics as non-steroid anti-inflammatory drugs opens a new insight in development of radioprotector. The drug has shown its potential radioprotective efficacy in clonogenic cell survival in Chinese hamster V79 cells with a DMF of 1.4. The pBR322 plasmid DNA gets damaged by radiation in which the supercoiled form gradually disappears with increasing radiation dose. Diclofenac sodium has shown its radioprotective potential by scavenging radiation induced free radicals which are depicted by its ability in restoring the fraction of supercoiled form of plasmid DNA back to normal. 250μM concentration of the drug provides GSSB yield of 3.65±0.5×10−9Da−1Gy−1. This drug has shown to have a free radical scavenging activity because the radical cation with blue color is converted to the colorless neutral form by addition of diclofenac sodium in ABTS assay. Whole body survival study has shown it to protect 45.5% of C57BL/6 mice at a lethal irradiation dose of 9Gy. Therefore, this molecule offers a potential radioprotective ability besides being used routinely as analgesic and anti inflammatory compound.

Reply to P. Bhandari

All the authors thank Dr. Bhandari for comments on our recently published review, Normal tissue protection for improving radiotherapy: where are the gaps? We agree that opportunities for discovery and development of radioprotectors and mitigators include plant sources, which is an underexplored area. Our paper wasn’t intended to be an exhaustive review of radioprotectors/mitigators, but rather to present examples of important adverse effects of radiation therapy and current approaches and limitations of using radioprotectors/mitigators to improve treatment outcome and quality of life. Exploration of plant sources for radioprotective properties presents both scientific and economic opportunities and challenges, as noted by Dr. Bhandari.

The Prostaglandin E 1 Analog, Misoprostol, a Normal Tissue Protector, Does Not Protect Four Murine Tumors In Vivo from Radiation Injury

The clinical development of radioprotectors, such as misoprostol, to protect normal tissue during cancer treatment must proceed with the assurance that tumors are not protected similarly or significantly. To provide data on this critical question, radiation-induced growth delay with or without the presence of misoprostol was measured in four murine tumors grown in the flanks of mice: the Lewis lung carcinoma, M-5076 ovarian sarcoma, FSA and NFSA. The effect of misoprostol on the tumor control dose (TCD50) of radiation was measured in FSA-bearing mice with or without prior treatment with the nonsteroidal anti-inflammatory agent, indomethacin. Misoprostol did not influence the in vivo growth of any of the four tumors, nor did it protect any of the tumors from radiation-induced growth delay. Likewise, there was no increase in the radiation TCD50 to treat the FSA in vivo in control or indomethacin-treated tumor-bearing mice. To measure any possible influence of tumor burden on the protective effect of misoprostol on normal tissue in mice, the protective effect of misoprostol on the survival of intestinal clonogenic cells was measured in M-5076-bearing mice and found to be the same as in non-tumor-bearing mice. These data suggest that misoprostol protects normal tissue in mice without protecting at least four experimental murine tumors. The data support the contention that misoprostol can achieve therapeutic gain by protecting normal tissues without protecting tumors.