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Design and evaluation of a novel flavonoid-based radioprotective agent utilizing monoglucosyl rutin.Journal of Radiation Research May 2018In this study, three novel flavonoid composite materials, created by combining an aglycone [quercetin (QUE), hesperetin (HES) or naringenin (NAR)] with monoglucosyl...
In this study, three novel flavonoid composite materials, created by combining an aglycone [quercetin (QUE), hesperetin (HES) or naringenin (NAR)] with monoglucosyl rutin (MGR), were designed to test for improved radioprotectivity compared with that provided by administration of MGR alone. Aglycone in the MGR-composite state was highly soluble in water, compared with aglycone alone dissolved in dimethyl sulfoxide or distilled water. The antioxidant activity of the three flavonoid composites was as high as that of MGR only. Next, the cytotoxicity test after 30 min treatment of an MGR composite showed a clear reduction in cell viability and suggested that a rapid introduction of aglycone into cells had taken place. In addition, QUE/MGR and HES/MGR composites strongly scavenged intracellular reactive oxygen species (ROS) induced by X-ray irradiation as well as MGR alone did. However, in the colony-formation assay using irradiated Chinese hamster ovary (CHO) cells, the HES/MGR composite showed a stronger radioprotective effect than MGR alone did, but the QUE/MGR composite showed no additional protective effect compared with the control. Furthermore, it was revealed that QUE and QUE/MGR composite treatment had the effect of reducing the glutathione (GSH) content in cells, and that QUE showed a stronger inhibition of PARP activity compared that of HES and NAR. Our data demonstrated that when designing a flavonoid composite as a radioprotective agent, it was necessary to select an appropriate aglycone, considering not only its antioxidant ability but also its inhibitory effect on cell recovery or DNA repair after radiation injury.
Topics: Animals; Antioxidants; Biphenyl Compounds; CHO Cells; Cell Survival; Colony-Forming Units Assay; Cricetinae; Cricetulus; Flavonoids; Free Radical Scavengers; Glutathione; Intracellular Space; Picrates; Poly(ADP-ribose) Polymerases; Radiation-Protective Agents; Reactive Oxygen Species; Rutin; Solubility; Time Factors; Water
PubMed: 29373678
DOI: 10.1093/jrr/rrx090 -
Seminars in Radiation Oncology Jan 2019Symptomatic normal tissue injury is a common side effect following definitive therapeutic radiation and chemotherapy treatment for a variety of malignancies. These... (Review)
Review
Symptomatic normal tissue injury is a common side effect following definitive therapeutic radiation and chemotherapy treatment for a variety of malignancies. These cancer therapy related toxicities may occur acutely during treatment resulting in reduced or missed therapy agent administration or after the completion of therapy resulting in significant chronic morbidities that significantly diminish patient quality of life. Radiation and chemotherapy induce the formation of reactive oxygen species (ROS) both in normal tissues and tumor cells. One type of ROS common to both chemotherapy and radiation therapy is the formation of superoxide (O). Fortunately, due to metabolic differences between cancer and normal cell metabolism, as well as improved targeting techniques, ROS generation following radiation and chemotherapy is generally greater in cancer cells compared to normal tissues. However, the levels of ROS generated in normal tissues are capable of inducing significant toxicity. Thus, several groups are focusing on metabolism-based approaches to mitigate normal tissue effects occurring both during and following cancer therapy. This review will summarize the most current preclinical and clinical data available demonstrating the efficacy of small molecule, superoxide dismutase mimetics in minimizing radiation and chemotherapy-induced normal tissue injury, resulting in enhanced patient outcomes.
Topics: Biomimetic Materials; Humans; Neoplasms; Radiation-Protective Agents; Radiation-Sensitizing Agents; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 30573187
DOI: 10.1016/j.semradonc.2018.10.005 -
Expert Opinion on Drug Discovery Jul 2017Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models,... (Review)
Review
Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans. Area covered: The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys. Expert opinion: The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes for NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.
Topics: Acute Radiation Syndrome; Animals; Disease Models, Animal; Drug Approval; Drug Design; Drug Discovery; Humans; Macaca mulatta; Primates; Radiation-Protective Agents; United States; United States Food and Drug Administration
PubMed: 28441902
DOI: 10.1080/17460441.2017.1323863 -
Roczniki Panstwowego Zakladu Higieny 2013Public feelings concerning radiation are still controversy. The main sources of trouble seems to be the failure nuclear power plant and danger of terroristic attack,... (Review)
Review
Public feelings concerning radiation are still controversy. The main sources of trouble seems to be the failure nuclear power plant and danger of terroristic attack, which may cause temporally enhanced level of radiation leading to harmful health effects. Since radiation induced cellular damage is attributed primarily to harmful effect of free radicals, molecules with direct free radical scavenging properties are particularly promising as radiation modifiers/protectors, i.e. agents which present prior to or shortly after radiation exposure alter to response of tissues to radiation. Unfortunately, some of known radioprotectors are toxic at doses required for radioprotection. Resveratrol (RSV), an natural polyphenol is produced in several plants in response to injury, stress, bacteria or fungi infection, UV-irradiation and exposure to ozone. It is present in human diet i.e. in fruits and in wine. RSV is known for its antioxidant, anti-inflammatory, analgesic, antiviral, cardioprotective, neuroprotective and antiageing action and it has been shown to have chemopreventive effects with respect to several human disease such as cardiovascular disease, osteoporosis and gastric ulcers. Depending on the dose, RSV may act as antioxidant or as pro-oxidant. RSV improves sperm count and motility in rodents and prevent DNA damage caused by cryptopreservation of human sperm. Moreover, RSV acting with other agents, inhibits the toxic action of them. There are evidences that RSV is able to modulate the behavior of cells in response to radiation induced damage. Minimalization of radiation induced damage to somatic and germ cells by RSV might be useful in cancer therapy to prevent the damage to normal cells as well as in case of radiological accidents.
Topics: Antioxidants; Cell Survival; DNA Damage; Humans; Oxidation-Reduction; Radiation Injuries; Radiation-Protective Agents; Resveratrol; Stilbenes
PubMed: 24693709
DOI: No ID Found -
Molecules (Basel, Switzerland) Oct 2009The essential trace element selenium, which is a crucial cofactor in the most important endogenous antioxidative systems of the human body, is attracting more and more... (Review)
Review
The essential trace element selenium, which is a crucial cofactor in the most important endogenous antioxidative systems of the human body, is attracting more and more the attention of both laypersons and expert groups. The interest of oncologists mainly focuses in the following clinical aspects: radioprotection of normal tissues, radiosensitizing in malignant tumors, antiedematous effect, prognostic impact of selenium, and effects in primary and secondary cancer prevention. Selenium is a constituent of the small group of selenocysteine-containing selenoproteins and elicits important structural and enzymatic functions. Selenium deficiency has been linked to increased infection risk and adverse mood states. It has been shown to possess cancer-preventive and cytoprotective activities in both animal models and humans. It is well established that Se has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism and protection against DNA damage. Recent clinical trials have shown the importance of selenium in clinical oncology. Our own clinical study involving 48 patients suggest that selenium has a positive effect on radiation-associated secondary lymphedema in patients with limb edemas, as well as in the head and neck region, including endolaryngeal edema. Another randomized phase III study of our group was performed to examine the cytoprotective properties of selenium in radiation oncology. The aim was to evaluate whether sodium selenite is able to compensate a preexisting selenium deficiency and to prevent radiation induced diarrhea in adjuvant radiotherapy for pelvic gynecologic malignancies. Through this study, the significant benefits of sodium selenite supplementation with regards to selenium deficiency and radiotherapy induced diarrhea in patients with cervical and uterine cancer has been shown for the first time in a prospective randomized trial. Survival data imply that supplementation with selenium does not interfere with the positive biological effects of radiation treatment and might constitute a valuable adjuvant therapy option especially in marginally supplied individuals. More recently there were emerging concerns coming up from two large clinical prevention trials (NPC, SELECT), that selenium increases the possible risk of developing diabetes type II. Despite obvious flaws of both studies and good counterarguments, a controversial debate remains on the possible advantage and risks of selenium in cancer prevention. However, in the light of the recent clinical trials the potential benefits of selenium supplementation in tumor patients are undeniable, even if further research is needed.
Topics: Cytoprotection; Humans; Lymphedema; Neoplasms; Radiation-Protective Agents; Randomized Controlled Trials as Topic; Selenium
PubMed: 19924043
DOI: 10.3390/molecules14103975 -
International Journal of Molecular... May 2016The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of... (Review)
Review
The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and Drug Administration (U.S. FDA) has approved only two growth factors, Neupogen (granulocyte colony-stimulating factor (G-CSF), filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy Rule. Promising radioprotective efficacy results of γ-tocotrienol (GT3; a member of the vitamin E family) in the mouse model encouraged its further evaluation in the nonhuman primate (NHP) model. These studies demonstrated that GT3 significantly aided the recovery of radiation-induced neutropenia and thrombocytopenia compared to the vehicle controls; these results particularly significant after exposure to 5.8 or 6.5 Gray (Gy) whole body γ-irradiation. The stimulatory effect of GT3 on neutrophils and thrombocytes (platelets) was directly and positively correlated with dose; a 75 mg/kg dose was more effective compared to 37.5 mg/kg. GT3 was also effective against 6.5 Gy whole body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a single administration of GT3 without any supportive care was equivalent, in terms of improving hematopoietic recovery, to multiple doses of Neupogen and two doses of Neulasta with full supportive care (including blood products) in the NHP model. GT3 may serve as an ultimate radioprotector for use in humans, particularly for military personnel and first responders. In brief, GT3 is a promising radiation countermeasure that ought to be further developed for U.S. FDA approval for the ARS indication.
Topics: Acute Radiation Syndrome; Animals; Blood Platelets; Chromans; Cytokines; Drug Evaluation, Preclinical; Humans; Neutrophils; Radiation-Protective Agents; Vitamin E
PubMed: 27153057
DOI: 10.3390/ijms17050663 -
Advances in Experimental Medicine and... 2008Antioxidants have been studied for their capacity to reduce the cytotoxic effects of radiation in normal tissues for at least 50 years. Early research identified... (Review)
Review
Antioxidants have been studied for their capacity to reduce the cytotoxic effects of radiation in normal tissues for at least 50 years. Early research identified sulfur-containing antioxidants as those with the most beneficial therapeutic ratio, even though these compounds have substantial toxicity when given in-vivo. Other antioxidant molecules (small molecules and enzymatic) have been studied for their capacity to prevent radiation toxicity both with regard to reduction of radiation-related cytotoxicity and for reduction of indirect radiation effects including long-term oxidative damage. Finally, categories of radiation protectors that are not primarily antioxidants, including those that act through acceleration of cell proliferation (e.g. growth factors), prevention of apoptosis, other cellular signaling effects (e.g. cytokine signal modifiers), or augmentation of DNA repair, all have direct or indirect effects on cellular redox state and levels of endogenous antioxidants. In this review we discuss what is known about the radioprotective properties of antioxidants, and what those properties tell us about the DNA and other cellular targets of radiation.
Topics: Animals; Antioxidants; DNA Damage; Humans; Radiation Injuries; Radiation, Ionizing; Radiation-Protective Agents
PubMed: 18290327
DOI: 10.1007/978-0-387-74911-2_20 -
The Oncologist Jun 2007After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been... (Review)
Review
After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug Administration has approved the i.v. use of amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Nonetheless, amifostine has potential applications in many other oncologic settings. Novel schedules and routes of administration are under investigation and may further simplify the use of amifostine, reduce any undesired effects, and considerably broaden its applications. This review summarizes the clinical experience with amifostine and provides insight into future clinical directions.
Topics: Amifostine; Humans; Mucositis; Neoplasms; Radiation-Protective Agents; Radiotherapy; Treatment Outcome; Xerostomia
PubMed: 17602063
DOI: 10.1634/theoncologist.12-6-738 -
The Journal of Medical Investigation :... 2019Radiation damage to normal tissues is a serious concern in radiation therapy. Advances in radiotherapeutic technology have improved the dose distribution of the target... (Review)
Review
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.
Topics: Apoptosis; Chelating Agents; Chloroquinolinols; Drug Development; Humans; Radiation Tolerance; Radiation-Protective Agents; Tumor Suppressor Protein p53
PubMed: 31656277
DOI: 10.2152/jmi.66.219 -
Asian Pacific Journal of Cancer... 2013Cochlea hair cell death is regarded to be responsible for the radiation-induced sensorineural hearing loss (SNHL), which is one of the principal complications of... (Review)
Review
Cochlea hair cell death is regarded to be responsible for the radiation-induced sensorineural hearing loss (SNHL), which is one of the principal complications of radiotherapy (RT) for head and neck cancers. In this mini- review, we focus on the current progresses trying to unravel mechanisms of radiation-induced hair cell death and find out possible protection. P53, reactive oxygen species (ROS) and c-Jun N-terminal kinase (JNK) pathways have been proposed as pivotal in the processes leading to radiation hair cell death. Potential protectants, such as amifostine, N-acetylcysteine (NAC) and epicatechin (EC) , are claimed to be effective at reducing radiation- inducedhair cell death. The RT dosage, selection and application of concurrent chemotherapy should be pre- examined in order to minimize the damage to cochlea hair cells.
Topics: Animals; Cell Death; Cochlea; Hair Cells, Auditory; Humans; Radiation-Protective Agents; Radiotherapy
PubMed: 24289554
DOI: 10.7314/apjcp.2013.14.10.5631