Targeting the CXCL12/CXCR4 pathway to reduce radiation treatment side effects.

High precision, image-guided radiotherapy (RT) has increased the therapeutic ratio, enabling higher tumor and lower normal tissue doses, leading to improved patient outcomes. Nevertheless, some patients remain at risk of developing serious side effects.In many clinical situations, the radiation tolerance of normal tissues close to the target volume limits the dose that can safely be delivered and thus the potential for tumor control and cure. This is particularly so in patients being re-treated for tumor progression or a second primary tumor within a previous irradiated volume, scenarios that are becoming more frequent in clinical practice.Various normal tissue 'radioprotective' drugs with the potential to reduce side effects have been studied previously. Unfortunately, most have failed to impact clinical practice because of lack of therapeutic efficacy, concern about concurrent tumor protection or excessive drug-related toxicity. This review highlights the evidence indicating that targeting the CXCL12/CXCR4 pathway can mitigate acute and late RT-induced injury and reduce treatment side effects in a manner that overcomes these previous translational challenges. Pre-clinical studies involving a broad range of normal tissues commonly affected in clinical practice, including skin, lung, the gastrointestinal tract and brain, have shown that CXCL12 signalling is upregulated by RT and attracts CXCR4-expressing inflammatory cells that exacerbate acute tissue injury and late fibrosis. These studies also provide convincing evidence that inhibition of CXCL12/CXCR4 signalling during or after RT can reduce or prevent RT side effects, warranting further evaluation in clinical studies. Greater dialogue with the pharmaceutical industry is needed to prioritize the development and availability of CXCL12/CXCR4 inhibitors for future RT studies.

Scleroglucan protects the intestine from irradiation-induced injury by targeting the IL-17 signaling pathway.

BACKGROUND: Intestinal tissue is extremely sensitive to ionizing radiation (IR), which is easy to cause intestinal radiation sickness, and the mortality rate is very high after exposure. Recent studies have found that intestinal immune cells and intestinal stem cells (ISCs) may play a key role in IR-induced intestinal injury. METHODS: C57BL6 mice matched for age, sex and weight were randomly grouped and intraperitoneal injected with PBS, Scleroglucan (125.0 mg/kg) or Anti-mouse IL-17A -InVivo (10 mg/kg), the number of mice in each group was n ≥ 3.Survival time, body weight, pathology, organoids and immune cell markers of the mice after IR (10.0 Gy) were compared, and the mechanism of action in intestinal tissues was verified by transcriptome sequencing. RESULTS: Scleroglucan has significant radiation protective effects on the intestine, including improving the survival rate of irradiated mice, inhibiting the radiation damage of intestinal tissue, and promoting the proliferation and differentiation of intestinal stem cells (ISCs). The results of RNA sequencing suggested that Scleroglucan could significantly activate the immune system and up-regulate the IL-17 and NF-κB signaling pathways. Flow cytometry showed that Scleroglucan could significantly up-regulate the number of Th17 cells and the level of IL-17A in the gut. IL-17A provides radiation protection. After intraperitoneal injection of Scleroglucan and Anti-mouse IL-17A -InVivo, mice can significantly reverse the radiation protection effect of Scleroglucan, down-regulate the molecular markers of intestinal stem cells and the associated markers of DC, Th1 and Th17 cells, and up-regulate the associated markers of Treg and Macrophage cells. CONCLUSION: Scleroglucan may promote the proliferation and regeneration of ISCs by regulating the activation of intestinal immune function mediated by IL-17 signaling pathway and play a protective role in IR-induced injury.

Development of Drug Products for the Treatment of Acute Radiation Syndrome.

The Food and Drug Administration's (FDA) approval to market drug products for use as medical countermeasures, to prevent or mitigate injury caused by various threat agents, is commonly based on evidence of efficacy obtained in animals. Animal studies are necessary when human studies are not feasible and challenge studies are not ethical. The successful development of countermeasures to radio-nuclear threats that cause Acute Radiation Syndrome (ARS) provides the opportunity to explore potential areas of overlap in the scientific approaches to studies of injuries caused by radiation and sulfur mustard exposures in animals. The aim is to evaluate the available scientific knowledge for radiation threat agents and sulfur mustard for potential analogies of fundamental mechanisms of organ injury and dysfunction. This evaluation is needed to determine the applicability of regulatory strategies for product development and approval adopted by manufacturers of countermeasures for radiation threat agents. Key elements of an efficient development plan based on animal efficacy studies include characterizing the pathophysiology of organ injury and the mechanism of action (MOA) of the countermeasure; modeling the clinical condition in animals to establish the manifestations of the injury caused by various levels of exposures to the threat agent and the response to various doses of the countermeasure candidate; as well as selecting a maximally effective human dose.

Evaluating the radioprotective effect of green barley juice on male rats.

PURPOSE: DNA damage accounts for most biological effects of ionizing radiation. Antioxidants are known for their protective effect by preventing DNA damage. This pilot study aimed to evaluate the potential radioprotective effect of Natural SOD®, a green barley juice rich in antioxidants, on DNA damage in the testes and lymphocytes of Wistar rats exposed to ionizing radiation. MATERIALS AND METHODS: Male Wistar rats (n = 15) were selected and equally divided into three groups. Rats in one of the groups were pretreated orally with Natural SOD® for 14 days, while rats in another group were sham-pretreated with saline solution. Rats in both these groups were afterwards subjected to a single dose of 6 Gy X-ray whole-body irradiation. The control group did not receive any treatment and was not irradiated. Shortly after X-ray exposure, all rats were sacrificed and testes and blood were collected. Gamma-H2AX and histopathological assessment in the testes, along with comet assay of lymphocytes were performed. RESULTS: Histopathological examination of the testes showed no significant architectural alterations. Immunofluorescent staining of γ-H2AX revealed more DNA double-strand break sites in testicular cells from sham animals compared to Natural SOD® pretreated rats. Alkaline comet assay results showed increased DNA damage in lymphocytes of irradiated rats compared to the control group with little differences between the pretreated groups. Animals pretreated with Natural SOD showed slightly reduced DNA damage compared to sham-pretreated rats. These findings suggest a potential protective effect of Natural SOD® against radiation-induced DNA damage. CONCLUSIONS: Natural SOD® exhibited a potential prophylactic radioprotective effect in rats, particularly in testes. Further investigations to determine medium and long-term effects of X-ray in animals administered Natural SOD® are needed to better estimate the radioprotective effect.

The potential value of 5-androstenediol in countering acute radiation syndrome.

Moderate-to-high doses of ionizing irradiation can lead to potentially life-threatening morbidities and increase mortality risk. In preclinical testing, 5-androstenediol has been shown to be effective in protecting against hematopoietic acute radiation syndrome. This agent is important for innate immunity, serves to modulate cell cycle progression, reduces radiation-induced apoptosis, and regulates DNA repair. The drug has been evaluated clinically for its pharmacokinetics and safety. The United States Food and Drug Administration granted investigational new drug status to its injectable depot formulation (NEUMUNE). Its safety and efficacy profiles make it an attractive candidate for further development as a radiation countermeasure.

Repurposing of FDA approved kinase inhibitor bosutinib for mitigation of radiation induced damage via inhibition of JNK pathway.

Radiotherapy is a common modality for cancer treatment. However, it is often associated with normal tissue toxicity in 20-80% of the patients. Radioprotectors can improve the outcome of radiotherapy by selectively protecting normal cells against radiation toxicity. In the present study, compound libraries containing 54 kinase inhibitors and 80 FDA-approved drugs were screened for radioprotection of lymphocytes using high throughput cell analysis. A second-generation FDA-approved kinase inhibitor, bosutinib, was identified as a potential radioprotector for normal cells. The radioprotective efficacy of bosutinib was evinced from a reduction in radiation induced DNA damage, caspase-3 activation, DNA fragmentation and apoptosis. Oral administration of bosutinib protected mice against whole body irradiation (WBI) induced morbidity and mortality. Bosutinib also reduced radiation induced bone-marrow aplasia and hematopoietic damage in mice exposed to 4 Gy and 6 Gy dose of WBI. Mechanistic studies revealed that the radioprotective action of bosutinib involved interaction with cellular thiols and modulation of JNK pathway. The addition of glutathione and N-acetyl cysteine significantly reduced the radioprotective efficacy of bosutinib. Moreover, bosutinib did not protect cancer cells against radiation induced toxicity. On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.

Development of radiation countermeasure agents for acute radiation syndromes.

The risk of internal and external exposure to ionizing radiation (IR) has increased alongside the development and implementation of nuclear technology. Therefore, serious security issues have emerged globally, and there has been an increase in the number of studies focusing on radiological prevention and medical countermeasures. Radioprotective drugs are particularly important components of emergency medical preparedness strategies for the clinical management of IR-induced injuries. However, a few drugs have been approved to date to treat such injuries, and the related mechanisms are not entirely understood. Thus, the aim of the present review was to provide a brief overview of the World Health Organization's updated list of essential medicines for 2023 for the proper management of national stockpiles and the treatment of radiological emergencies. This review also discusses the types of radiation-induced health injuries and the related mechanisms, as well as the development of various radioprotective agents, including Chinese herbal medicines, for which significant survival benefits have been demonstrated in animal models of acute radiation syndrome.

Radioprotective role of amifostine on osteointegration of titanium implants in the tibia of rats.

BACKGROUND: Titanium is the most widely used metal for bone integration, especially for cancer patients receiving ionizing radiation. This study aimed to investigate the amifostine administration that would reduce the effects of radiation on bone healing and osseointegration in rat models. OBJECTIVES: It is aimed that the application of amifostine in rats receiving radiotherapy treatment will reduce the negative effects of ionizing radiation on the bone. METHODS: Thirty-five adult male Wistar rats were randomly divided into one healthy and four experimental groups. In three consecutive days, two experimental groups of rats (AMF-RT-IMP and RT-IMP) were exposed to radiation (15 Gy/3 fractions of 5 Gy each). Then the titanium implants were inserted into the left tibia. Before the radiotherapy process, a 200 mg/kg dose of amifostine (AMF) was administered to the rats in the AMF-IMP and AMF-RT-IMP groups. Twenty-eight days after the screw implant, all rats were sacrificed, and their blood samples and tibia bones were collected for analysis. RESULTS: The results indicated an accelerated bone formation and a more rapid healing process in the screw implants in the AMF-IMP, AMF-RT-IMP, and AMF-RT groups than in the RT-IMP group. Also, bone-implant contact area measurement and inflammation decreased with amifostine treatment in the implants subjected to irradiation (p < 0.05). CONCLUSIONS: The results obtained in the present study suggested that amifostine prevents the losses of bone minerals, bone integrity, and implant position from ionizing-radiation when given before exposure.

[Research progress of irradiation injuries anti-agents].

Irradiation injuries anti-agents refer to drugs that can inhibit the initial stage of radiation injuries, or reduce the development of radiation injuries and promote the recovery of injuries when used early after irradiation exposure. According to the mechanism of action and the time of intervention, the irradiation injuries anti-agents are divided into four categories: radioprotectors, radiomitigators, radiation therapeutics for external radiation exposure, and anti-agents for internalized radionuclides. In this paper, the research progress of irradiation injuries anti-agents in recent years is reviewed.

Radioprotective countermeasures for radiation injury (Review).

A series of physiological and pathological changes occur after radiotherapy and accidental exposure to ionizing radiation (IR). These changes cause serious damage to human tissues and can lead to death. Radioprotective countermeasures are radioprotective agents that prevent and reduce IR injury or have therapeutic effects. Based on a good understanding of radiobiology, a number of protective agents have achieved positive results in early clinical trials. The present review grouped known radioprotective agents according to biochemical categories and potential clinical use, and reviewed radiation countermeasures, i.e., radioprotectors, radiation mitigators and radiotherapeutic agents, with an emphasis on their current status and research progress. The aim of the present review is to facilitate the selection and application of suitable radioprotectors for clinicians and researchers, to prevent or reduce IR injury.

Combination of natural polyphenols with a precursor of NAD+ and a TLR2/6 ligand lipopeptide protects mice against lethal γ radiation.

INTRODUCTION: Effective agents that could confer long-term protection against ionizing radiation in vivo would have applications in medicine, biotechnology, and in air and space travel. However, at present, drugs that can effectively protect against lethal ionizing radiations are still an unmet need. OBJECTIVE: To investigate if combinations of natural polyphenols, known for their antioxidant potential, could protect against ionizing radiations. METHODS: Plant-derived polyphenols were screened for their potential ability to confer radioprotection to mice given a lethal whole-body γ radiation (137Cs) dose expected to kill 50% of the animals in 30 days. Telomere and centromere staining, Q-FISH and comet assays were used to investigate chromosomal aberration, micronuclei formation and DNA breaks. Molecular oxidations were investigated by enzyme immunoassays and UPLC-MS/MS. RT-PCR, western blotting and siRNA-induced gene silencing were used to study signaling mechanisms and molecular interactions. RESULTS: The combination of pterostilbene (PT) and silibinin (SIL) was the most effective against γ-irradiation, resulting in 100% of the mice surviving at 30 days and 20% survival at one year. Treatment post γ-irradiation with two potential radiomitigators nicotinamide riboside (NR, a vitamin B3 derivative), and/or fibroblast-stimulating lipoprotein 1 (FSL1, a toll-like receptor 2/6 agonist), did not extend survival. However, the combination of PT, SIL, NR and FSL1 achieved a 90% survival one year post γ-irradiation. The mechanism involves induction of the Nrf2-dependent cellular antioxidant defense, reduction of NF-kB signaling, upregulation of the PGC-1α/sirtuins 1 and 3 axis, PARP1-dependent DNA repair, and stimulation of hematopoietic cell recovery. The pathway linking Nrf2, sirtuin 3 and SOD2 is key to radioprotection. Importantly, this combination did not interfere with X-ray mediated killing of different tumor cells in vivo. CONCLUSION: The combination of the radioprotectors PT and SIL with the radiomitigators NR and FSL1 confer effective, long-term protection against γ radiation in vivo. This strategy is potentially capable of protecting mammals against ionizing radiations.

Review of compounds that exhibit radioprotective and/or mitigatory effects after application of diagnostic or therapeutic ionizing radiation.

PURPOSE: Exposure to ionizing radiation can be accidental or for medical purposes. Analyzes of the frequency of radiation damage in the general population, it has been determined that by far the most common are those that occur as a result of diagnostic or therapeutic procedures. Damage caused by radiation, either accidentally or for therapeutic purposes, can be reduced by the use of radioprotectors, mitigators or other therapeutic agents. A detailed research of the available literature shows that there is little systematized data of potentially radioprotective and/or mitigating effects of drugs from the personal therapy of patients during the application of therapeutic ionizing radiation. The aim of this paper is to present review of compounds, especially personal therapy drugs, that exhibit radioprotective and/or mitigating effects after the application of diagnostic or therapeutic ionizing radiation. CONCLUSIONS: Given the widespread use of ionizing radiation for diagnostic and therapeutic purposes, there is a clear need to create a strategy and recommendations of relevant institutions for the use of radioprotectors and mitigators in everyday clinical practice, with individual evaluation of the patient's condition and selection of the compounds that will show the greatest benefit in terms of radioprotection.

Radioprotective effect of mistletoe extract on intestinal toxicity: in vivo study using adult zebrafish.

PURPOSE: The intestine is a dose-limiting organ in the treatment of intra-abdominal cancer. We previously reported that the extract of mistletoe parasites on Quercus had a more potent radioprotective effect than amifostine in reducing the developmental toxicities of zebrafish embryos. In this study, radioprotection against intestinal toxicity was investigated in adult zebrafish. METHODS: Wild-type adult AB zebrafish were exposed to 45-50 Gy of photon beam irradiation and/or treated with mistletoe extract orally 1 h before. The main endpoints of the study were survival and degree of deformation of the intestinal villi. RESULTS: The median follow-up period was 10 d post-irradiation (range: 7-11 d). A total of 105 zebrafish were used, including 42 in the radiation alone, 42 in the radiation and mistletoe arms, and 21 control subjects (mistletoe alone, mock-irradiated arm). The rate of both significant deformity and death was 53% in the radiation-alone arm, whereas the corresponding rate was 30% in the radiation and mistletoe arms. Significant deformity-free survival rates at 10 d post-irradiation in the radiation alone, and radiation and mistletoe arms were 44.7% (95% confidence interval [CI]:20-54.3) and 68.4% (95% CI:53.8-86.8), respectively (p=.046). The radiation and mistletoe arms showed decreased expression of two of three inflammatory genes (IL-1ß and IL-6) compared to the radiation alone group (p<.05). CONCLUSION: The radioprotective effect against intestinal toxicity was successfully shown in an adult zebrafish model. This result suggests the possibility of clinical use of mistletoe extract for the treatment of abdominal cancers.

Research progress of irradiation injuries anti-agents / 中华劳动卫生职业病杂志

Irradiation injuries anti-agents refer to drugs that can inhibit the initial stage of radiation injuries, or reduce the development of radiation injuries and promote the recovery of injuries when used early after irradiation exposure. According to the mechanism of action and the time of intervention, the irradiation injuries anti-agents are divided into four categories: radioprotectors, radiomitigators, radiation therapeutics for external radiation exposure, and anti-agents for internalized radionuclides. In this paper, the research progress of irradiation injuries anti-agents in recent years is reviewed.

CLASSIFICATION OF MEDICAL EQUIPMENT FOR ANTI-RADIATION PROTECTION. / KLASYFIKATsIIa MEDYChNYKh ZASOBIV PROTYRADIATsIINOGO ZAKhYSTU.

Any collection of objects of study needs some arrangement, i. e. classification. The existing numerous classifications of antiradiation agents are built on the basis of their antiradiation effects of an integrated or differentiated nature. The work presents the chronology of the main classifications of chemical compounds that are able to protect against the shortterm and longterm effects of ionizing radiation when they are introduced into the body both before and after exposure. The change of views, trends and paradigms regarding radioprotective compounds is shown. These classifications of antiradiation medicines include radioprotectors, means of stimulating the radioresistance of the body, means of prevention and suppression of the primary reaction to irradiation, means of prevention and treatment of lesions from exposure to incorporated radionuclides, means of treatment of acute bone marrow syndrome, means of treatment of local radiation lesions. It is shown that modern concepts of radiation protection are based on fundamentally different «points of application¼ of groups of radioprotective agents and depend on the stage of radiation damage.

Protection of the hematopoietic system against radiation-induced damage: drugs, mechanisms, and developments.

Sometimes, people can be exposed to moderate or high doses of radiation accidentally or through the environment. Radiation can cause great harm to several systems within organisms, especially the hematopoietic system. Several types of drugs protect the hematopoietic system against radiation damage in different ways. They can be classified as "synthetic drugs" and "natural compounds." Their cellular mechanisms to protect organisms from radiation damage include free radical-scavenging, anti-oxidation, reducing genotoxicity and apoptosis, and alleviating suppression of the bone marrow. These topics have been reviewed to provide new ideas for the development and research of drugs alleviating radiation-induced damage to the hematopoietic system.

Effects of Gamma-Tocotrienol on Intestinal Injury in a GI-Specific Acute Radiation Syndrome Model in Nonhuman Primate.

The gastrointestinal (GI) system is highly susceptible to irradiation. Currently, there is no Food and Drug Administration (FDA)-approved medical countermeasures for GI radiation injury. The vitamin E analog gamma-tocotrienol (GT3) is a promising radioprotector in mice and nonhuman primates (NHP). We evaluated GT3-mediated GI recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques were divided into two groups; eight received vehicle and eight GT3 24 h prior to 12 Gy TBI. Proximal jejunum was assessed for structural injuries and crypt survival on day 4 and 7. Apoptotic cell death and crypt cell proliferation were assessed with TUNEL and Ki-67 immunostaining. Irradiation induced significant shortening of the villi and reduced mucosal surface area. GT3 induced an increase in crypt depth at day 7, suggesting that more stem cells survived and proliferated after irradiation. GT3 did not influence crypt survival after irradiation. GT3 treatment caused a significant decline in TUNEL-positive cells at both day 4 (p < 0.03) and 7 (p < 0.0003). Importantly, GT3 induced a significant increase in Ki-67-positive cells at day 7 (p < 0.05). These data suggest that GT3 has radioprotective function in intestinal epithelial and crypt cells. GT3 should be further explored as a prophylactic medical countermeasure for radiation-induced GI injury.

1-Isobutanoil-2-isopropylisothiourea Phosphate, T1082: A Safe and Effective Prevention of Radiotherapy Complications in Oncology.

The radioprotective effects of a new 1-isobutanoil-2-isopropylisothiourea derivative named T1082 are presented. Research methods included toxic characteristics, radioprotective activity (Till-McCulloch's test and 30-day survival test) in γ-ray total-body-irradiated mice, and a clinical and histological study of the effect of T1082 on acute radiation skin reactions (RSR) in rats after a single or fractionated ß-ray local irradiation. T1082 is more effective than its analogue, the NOS inhibitor T1023, at low concentrations and doses (1/12-1/8 LD10), both parenterally and intragastrically. In this case, its therapeutic index (LD50/ED50) reaches 30, and the optimal radioprotective doses (ED84-98-141-224 mg/kg) are an order less than the maximum tolerated doses-1/16-1/10 LD10. These properties allowed T1082, at a low intragastrical dose (160 mg/kg; 1/14 LD10), to significantly limit the severity of acute RSR after single (40 Gy) and fractionated (78 Gy) ß-ray irradiation. The results confirm T1082 as one of the safest emergency radioprotectors and indicate the prospects for its further development as a pharmacological agent for the prevention of RT complications.

Microalgae-based oral microcarriers for gut microbiota homeostasis and intestinal protection in cancer radiotherapy.

Protecting the whole small intestine from radiation-induced intestinal injury during the radiotherapy of abdominal or pelvic solid tumors remains an unmet clinical need. Amifostine is a promising selective radioprotector for normal tissues. However, its oral application in intestinal radioprotection remains challenging. Herein, we use microalga Spirulina platensis as a microcarrier of Amifostine to construct an oral delivery system. The system shows comprehensive drug accumulation and effective radioprotection in the whole small intestine that is significantly superior to free drug and its enteric capsule, preventing the radiation-induced intestine injury and prolonging the survival without influencing the tumor regression. It also shows benefits on the gut microbiota homeostasis and long-term safety. Based on a readily available natural microcarrier, this work presents a convenient oral delivery system to achieve effective radioprotection for the whole small intestine, providing a competitive strategy with great clinical translation potential.

Gamma-tocotrienol, a radiation countermeasure, reverses proteomic changes in serum following total-body gamma irradiation in mice.

Radiological incidents or terrorist attacks would likely expose civilians and military personnel to high doses of ionizing radiation, leading to the development of acute radiation syndrome. We examined the effectiveness of prophylactic administration of a developmental radiation countermeasure, γ-tocotrienol (GT3), in a total-body irradiation (TBI) mouse model. CD2F1 mice received GT3 24 h prior to 11 Gy cobalt-60 gamma-irradiation. This dose of radiation induces severe hematopoietic acute radiation syndrome and moderate gastrointestinal injury. GT3 provided 100% protection, while the vehicle control group had 100% mortality. Two-dimensional differential in-gel electrophoresis was followed by mass spectrometry and Ingenuity Pathway Analysis (IPA). Analysis revealed a change in expression of 18 proteins in response to TBI, and these changes were reversed with prophylactic treatment of GT3. IPA revealed a network of associated proteins involved in cellular movement, immune cell trafficking, and inflammatory response. Of particular interest, significant expression changes in beta-2-glycoprotein 1, alpha-1-acid glycoprotein 1, alpha-2-macroglobulin, complement C3, mannose-binding protein C, and major urinary protein 6 were noted after TBI and reversed with GT3 treatment. This study reports the untargeted approach, the network, and specific serum proteins which could be translated as biomarkers of both radiation injury and protection by countermeasures.