|Year : 2016 | Volume
| Issue : 4 | Page : 1234-1242
Prophylactic role of some plants and phytochemicals against radio-genotoxicity in human lymphocytes
Mohsen Cheki1, Ehsan Mihandoost2, Alireza Shirazi1, Aziz Mahmoudzadeh3
1 Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Radiology and Medical Physics, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
3 Novin Medical Radiation Institute, Tehran, Iran
|Date of Web Publication||7-Feb-2017|
Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Keshavarz Boulevard, Poursina Avenue, Tehran
Source of Support: None, Conflict of Interest: None
Genotoxicity in lymphocytes of cancer patients undergoing radiotherapy can lead to lymphocytopenia. Lymphocytopenia induced by radiotherapy is one of the most unfavorable prognostic biological markers in cancer patients, since it has been accepted to be associated with poor prognosis in terms of both survival time and response to cancer therapy. Therefore, reduction in lymphocytopenia may increase treatment efficiency. Research endeavors with synthetic radioprotectors in the past have met with little success primarily due to toxicity-related problems. These disadvantages have led to interest on the use of some plants and phytochemicals as radioprotector. The aim of this paper is to review protective role of some plants and phytochemicals against genotoxicity-induced by ionizing radiation in human blood lymphocytes. Therefore, current review may help the future researches to decrease lymphocytopenia in radiotherapeutic clinical trials.
Keywords: Genotoxicity, human lymphocytes, ionizing radiation, phytochemicals, plants
|How to cite this article:|
Cheki M, Mihandoost E, Shirazi A, Mahmoudzadeh A. Prophylactic role of some plants and phytochemicals against radio-genotoxicity in human lymphocytes. J Can Res Ther 2016;12:1234-42
|How to cite this URL:|
Cheki M, Mihandoost E, Shirazi A, Mahmoudzadeh A. Prophylactic role of some plants and phytochemicals against radio-genotoxicity in human lymphocytes. J Can Res Ther [serial online] 2016 [cited 2017 Dec 11];12:1234-42. Available from: http://www.cancerjournal.net/text.asp?2016/12/4/1234/172131
| > Introduction|| |
Exposure of living systems to ionizing radiation (IR) leads to the formation of reactive oxygen species (ROS) and reactive nitrogen species. These reactive species impose damage to the various bio-macromolecules such as DNA, lipids, and proteins present in the cell., It is known that human lymphocytes, the most important white blood cells, are very sensitive to IR. It has been reported that IR caused DNA damage in human peripheral blood lymphocytes (HPBLs) which can lead to cell death or genomic instability., The decrease in peripheral leukocyte count, particularly lymphocyte, following radiation therapy (RT) has been widely reported. Lymphocytopenia represents one of the most evident side effects of RT, particularly in the case of pelvis cancer, which negatively influence the efficacy of RT.,,,,, Thus, lymphocytopenia decrement may result in an effective treatment. Radioprotectors are compounds that have the ability to decrease the biological effects of IR on normal cells and tissues, including lethality, mutagenicity, and carcinogenicity. Although radioprotectors may provide the opportunity to decrease harmful effects of RT, few radioprotective agents are in clinical use primarily due to undesirable side effects such as hypotension, vomiting, nausea, sneezing, hot flashes, mild somnolence, and hypocalcemia., Therefore, the search for radioprotectors with less toxicity must continue with increased excitement for find new agents that can protect against radiation-induced damage in healthy organs. Extensive studies of plants and phytochemicals have shown that these compounds have protective effects against radiation damages with fewer side effects., This review emphasizes on the state of knowledge about plants and phytochemicals were used in order to reduce genotoxicity induced by IR in HPBL.
| > Critical Target of Radiation|| |
The main target of IR is DNA, a macromolecule with well-known double helix structure, consisting of two strands held together by hydrogen bonds between the bases. IR causes DNA damage via two different ways, namely indirect and direct effects. The indirect effect refers to the interaction of hydroxyl radicals from water radiolysis with the local molecules surrounding and/or on the DNA, whereas the direct effects result from the ionizations that create sites of radical cations, radical anions, and excitations.,, Upon the interaction of IR and cells, more than half (about 60%) of the IR energy deposited in the cell is initially absorbed by water in the cytosol because the eukaryotic cell contains 70–80% water molecules, the majority of which are found in the cytosol and thus form the hydration layers of the cellular structural components and macromolecules. Subsequently combined with the indirect effect of radicals resulting from water radiolysis in the cytoplasm, the remaining energy (<40%) may significantly damage DNA in the nuclei.,
IR induces a wide variety of lesions that can cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Single strand breaks (SSBs) are of little biological significance as regards cell killing, as they are readily repaired using the opposite stand as a template. However, if the repair is incorrect (mispair), it may result in mutation. Double strand breaks (DSBs) are thought to be the most harmful of IR-induced lesions and occur when breaks in the two strands are opposite to one another, or separated by only a few base pairs. IR also induces other forms of DNA damage including cross-links, oxidative base modification, and clustered base damage.,, The numbers of DNA lesions per cell that are reported immediately after a radiation dose of 1 Gy have been estimated to be approximately >1000 base damage, 1000 SSBs, 40 DSBs, 20 DNA–DNA cross-links, 150 DNA–protein cross-links, and 160–320 non-DSB clustered DNA damage.,, Failure to repair DNA damage can have deleterious outcomes such cell death or genomic instability., Genomic instability has been studied by several indices, including analyses of chromosomal rearrangements and aberrations, gene amplification, aneuploidy, micronucleus formation, microsatellite instability, and gene mutations [Figure 1].,, Chromosomal instability is a well-characterized index of genomic instability that can persist for multiple generations after exposure to a range of genotoxic agents in a variety of mammalian cells.,,,, Natarajan et al. indicated that radiation-induced DSBs are mainly responsible for the formation of chromosomal aberrations (CAs). There are essentially three types of aberrations of radiated chromosomes in a mitotic cell namely, dicentric (DC), acentric fragments, and acentric rings, as a result of breakages and exchanges of chromatids. Damages to chromosomes are also demonstrated as micronuclei (MN) in rapidly proliferating cells. DSBs are repaired by either of the two mechanisms; the nonhomologous end joining pathway or homologous recombination pathway.,
|Figure 1: Radio-genotoxicity process and prophylactic role of radioprotectors|
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| > Human Peripheral Blood Lymphocyte: A recommended Target for Bio-Radioprotection Studies|| |
One approach to identify nontoxic and effective radioprotective compounds that can reduce adverse effects of IR are in vitro experiments, using human lymphocytes as a model system, because they are readily available, synchronized in G0, representative of averaged whole body radiation exposure, containing variety of redox, and free radical scavenging systems. In several studies, in vitro and in vivo, experiment on HPBL has been reported as a preferred model to understand the harmful effects of radiation in normal healthy cells. Monitoring of patients under radiotherapy for DNA damage could therefore contribute to the optimization of irradiation conditions and biological dosimetry.,, IR-induced DNA damage can be turned cytogenetic alterations such as CAs, MN, and sister chromatid exchanges (SCEs), interchanges of DNA replication products between sister chromatids at apparently homologous loci., Cytogenetic alterations induced by IR can be observed in HPBL within a few hours of exposure. Their frequency is related to the dose and quality of radiation and can be detected in blood samples taken long after the exposure.,
On the other hand, DNA damage in HPBL can lead to lymphocytopenia in cancer patients undergoing RT. Because of the fundamental role of lymphocytes in suppressing anticancer immunity, RT-induced lymphocytopenia could negatively influence the prognosis of cancer patients and the therapeutic efficacy of RT itself., Multivariate analyses have revealed a significant association between chemo-radiation-related lymphocytopenia and survival., Furthermore, Lissoni et al. demonstrated that pelvic RT-induced lymphocytopenia could negatively influence the efficacy of RT itself and the decline in total lymphocyte number was also significantly greater in patients who had no tumor regression in response to RT. Thus, lymphocytopenia reduction by radioprotectors may result in an improved response to cancer therapy and finally longer survival time. Famotidine is a specific, long-acting histamine H2-receptor antagonist with extensive use in the treatment of peptic ulcers. Experimental studies have shown that famotidine exert radioprotective effects on radiation-induced MN and CAs in HPBL. Razzaghdoust et al. have reported that oral administration of famotidine tablets (40 mg) twice daily, 4 and 3 h before each RT fraction significantly reduced radiation-induced lymphocytopenia in prostate cancer patients. Hence, in vitro and ex vivo assessment of radioprotectors against cytogenetic alterations induced by IR in HPBL will be necessary, before administration of these compounds to cancer patients undergoing RT in order to lymphocytopenia decrement.
| > Ideal Radioprotector|| |
An ideal radioprotector should be readily available, inexpensive, does not have toxic implications in a wide dose range, and have compatibility with the wide range of other drugs that will be available to patients or personnel, shelf-life should be long, easy handling and storage, absence of cumulative effect in repeated administration, orally administered, ability of fast resorption, and distribution in tissue and organs, have a general protective effect on the majority of organs, radiosensitive for tumor cells, efficacy for different types of radiation (X, gamma, electrons and neutrons), efficacy in joined and fraction radiation, act in a wide time-window to render protection, protect all populations at risk, possesses a reasonably good dose reduction factor, and can act through multiple mechanisms.,,
| > Tendency Process to Plants and Phytochemicals as Radioprotector|| |
Advances in radiation sciences, particularly the understanding of radiation effects on biological systems, have paved the way toward the development of radioprotective compounds that can be effectively utilized to achieve protection against the deleterious effects of IR. Research and development on radioprotective drugs started nearly 60 years ago. In 1949, Patt et al. were the first to investigate the radioprotective effect of amino-acid cysteine when exposed to lethal doses of X-rays. For almost three decades, the Walter Reed Army Research Institute synthesized and tested over 4000 compounds in an attempt to find a useful radioprotector, one that would protect against IR without toxic side effects. The most effective compound of this type, originally tested against lethal doses of X-rays and γ-rays in mice, is WR-2721, the common name of which is amifostine. Amifostine selectively protects a broad range of normal tissues, including the oral mucosa, salivary glands, lungs, bone marrow, heart, intestines, and kidneys. Although amifostine was reported to be tolerated well in radiotherapeutic clinical trials, it was later found to have some undesirable side effects. These include hypotension, nausea, vomiting, diarrhoea, hypocalcemia, nephro- and neuro-toxicity, and allergy is the main problem related to use of it in patients and public during exposure to IR.,,,, The most side effects related to amifostine are dose-dependent. The major dose-limiting toxicity of amifostine is transient hypotension. Even at low doses used in RT close monitoring of blood pressure is required. Most patients receiving amifostine with RT require antiemetics., Moreover, amifostine has some disadvantages, such as limited routes of administration, narrow time windows for radioprotection, cost, and limited protection of the central nervous system. Because of the inherent toxicity of chemicals and synthetic agents at their effective radioprotective concentrations, investigators diverted their attention toward plants and phytochemicals as radioprotector. Plants (fruits, vegetables, and medicinal herbs) have been in use in several traditional systems of medicine for several hundreds and even thousands of years for treating various human ailments all over the world since they offer holistic treatment. Several of these plants have been reported to be beneficial for ameliorating free radical-mediated disease conditions in humans such as arthritis, atherosclerosis, cancer, Alzheimer's disease, Parkinson's disease, aging, and inflammatory disorders.,, Phytochemicals, as plant components with discrete bio-activities toward animal biochemistry and metabolism, are being widely examined for their ability to provide health benefits. Research supporting beneficial roles for phytochemicals against cancers, coronary heart disease, diabetes, high blood pressure, inflammation, microbial, viral and parasitic infections, psychotic diseases, spasmodic conditions, and ulcers. Therefore, screening of plants and phytochemicals offers a major focus for new drug discovery. In this way, attention over the past 20 years has shifted toward the evaluation of plant products as radioprotectors. Critical characteristics that may lead to the election of plants or phytochemicals for radioprotective researches include immunemodulatory, anti-inflammatory, antioxidant, antimicrobial, free radical scavenging, and anti-stress properties. The doses of plant and phytochemical preparations that were effective in radioprotection was significantly lower than the toxic dose and this is one of the major advantages of these preparations compared to synthetic compounds. Plants and phytochemicals were observed to diminish deleterious effects of IR when administered before irradiation.,,,,,Tinospora cordifolia (Family: Menispermaceae) finds a special mention for its use in tribal or folk medicine in different parts of the country.T. cordifolia root extract was administrated orally half an hour before a 2.5 Gy dose of gamma irradiation and was continued for 5 days consecutively at a dose of 75 mg/kg. This protocol effectively prevented radiation-induced alterations in body weight, tissue weight, weight index, tubular diameters, and anti-oxidative parameter viz., lipid peroxidation, glutathione (GSH), and catalase (CAT) activity in testes of mice.Acorus calamus L. (Family: Araceae), commonly known as sweet flag, is an important plant used in the ancient system of medicine. Sandeep and Nair  showed oral administration of A. calamus extract (ACE) to mice at a dose of 250 mg/kg 1 h before 2, 6, and 10 Gy gamma irradiation significantly increased the activities of major enzymes of the antioxidant defense system especially superoxide dismutase (SOD), CAT, GSH peroxidase (GPx), and levels of reduced GSH and malondialdehyde (MDA) and DNA strand breaks. It was also reported that ACE increased up to 5% survival rate in acute lethal dose of 10 Gy whole body γ-irradiation. Sandeep and Nair  in another study demonstrated that presence of ACE during irradiation prevented peroxidation of membrane lipids in mouse liver homogenate. It helped to reduce the disappearance of the covalently closed circular form of plasmid DNA following exposure to gamma irradiation. In addition, ACE effectively protected DNA from radiation-induced strand breaks and enhanced the DNA repair process. According to several phytochemical reports, salvianolic acid A (SAA) D (+)-(3, 4 dihydroxyphenyl) lactic acid is the principal effective, water-soluble constituent of Salvia miltiorrhiza Bunge (Family: Labiatae). Administration of SAA 1 h before 4 Gy gamma irradiation significantly reduced MN, comet assay parameters, γ-H2AX foci, thiobarbituric acid reactive substances level, and intracellular ROS in irradiated human normal intestinal epithelial cells (HIECs). It also significantly increased GSH and SOD levels and reduced MDA level in irradiated HIEC. SAA affected on repair of DNA damage with prompt and temporary increase in the expression of γ-H2AX at irradiated HIEC. SAA markedly increased expression of the pro-apoptotic proteins p53 and Bax and decreased the anti-apoptotic protein Bcl-2 in compared with the nonirradiated HIEC. Popov et al. demonstrated that haberlea rhodopensis extract injection (IM) to male rabbits, at a dose of 0.24 g/kg 2 h before 2 Gy gamma irradiation decreased the MDA level and increased SOD and CAT activity. Withania somnifera (L.) Dunal (ashwagandha, Indian ginseng, WS) is a perennial plant belonging to the order Solanaceae, is widely used in Ayurvedic medicine. When adult male rats received WS at a dose of 100 mg/kg for 7 consecutive days before exposure to 6 Gy of γ-irradiation, significantly reduced in serum hepatic enzymes, hepatic NO (x), MDA levels, DNA damage and significantly increased in SOD, GPx activities, and GSH content.
Further researches are needed to identify the herbal compounds responsible for radioprotective efficacy. Although there have been many plants evaluated for their ability to reduce radiation-induced damages in animals, their inadequate document at present to patronage their potential use in patients during RT.
| > Plants and Phytochemicals Against Radio-Genotoxicity in Human Peripheral Blood Lymphocyte|| |
Several studies have revealed that lymphocyte counts remain depressed years after the RT course.,,,, Hence, the reduction in DNA damage induced by IR in HPBL can lead to lymphocytopenia reduction., In the last 10 years, a significant increase seen in the use of plants and phytochemicals against IR-induced DNA damage in HPBL. These plants and phytochemicals decrease DNA damage by various mechanisms such as free radicals scavenging, reduced lipid peroxidation, increase of endogenous antioxidant defense, and enhanced DNA repair.,,, Plants and phytochemicals were evaluated against IR-induced DNA damage in HPBL with two methods. In the first method, plant or phytochemical administered orally in single nontoxic dose to healthy human volunteers and blood samples were collected in heparinized tubes before (−10 min) and 1, 2, and 3 h after the ingestion. At each of the collection times, for each volunteer, aliquots of heparinized whole blood were divided into two tubes of 1 ml. One tube was the control sample and another tube was irradiated at 37°C with X- or γ-rays., In the second method, blood samples or lymphocytes isolated from healthy human blood were incubated with plant or phytochemical for a ½–2 h. After incubation, blood samples or lymphocytes were irradiated at 37°C with X- or γ-rays.,,,
Davari et al. showed drink a decoction 4 g green tea in 280 ml boiling water for 5 constitutive days by healthy human volunteers and exposure of blood samples collected from volunteers to 2 Gy of gamma irradiation, resulted in a significant reduction of MN in compared with irradiated lymphocytes collected prior to drink. Pretreatment of human culture lymphocytes with ferulic acid, at doses of 1, 5, and 10 µg/ml 30 min before 1, 2, and 4 Gy gamma irradiation, statistically significant reduced MN and DC frequencies. Prasad et al. have reported sesamol (1, 5, and 10 µg/ml) treatment 30 min before 1, 2, and 4 Gy gamma irradiation significantly decreased MN and DC frequencies in irradiated HPBL. Mangifera indica (common name, mango) is a plant widely used in traditional medicine in different regions of the world. It is rich in polyphenols, where mangiferin is the main component. Treatment of human lymphocytes with M. indica L. (mango) stem bark aqueous extract (25 and 50 µg/ml) and mangiferin (5–25 µg/ml) 1 h before exposure to 5 Gy of γ-irradiation, resulted in reduced DNA damage (tail moment). Curcumin has radioprotective effects on normal cells, and it enhances radiation toxicity on tumor cells. The radioprotective activity of curcumin might not be due to single mechanism but to several mechanisms., The role of various concentration of curcumin was studied on the radiation-induced genotoxicity in HPBL. Treatment of HPBL with different doses (1, 5, and 10 µg/ml) of curcumin before exposure to 1, 2, and 4 Gy of gamma irradiation significantly reduced in frequency of MN and DC. In another study, Sebastia et al. showed that treatment of human lymphocytes with curcumin, at doses of 5, 50, and 500 μg/ml before 2 Gy gamma irradiation significantly decreased the frequency of DC, rings, acentrics, chromatid breaks, and gaps in irradiated lymphocytes. Moreover, maximum damage protection was reported at the concentration of 5 µg/ml. Al Suhaibani  have reported curcumin (5.0 μg/ml) treatment 30 min prior to 1 and 2 Gy of gamma irradiation significantly decreased SCE in irradiated HPBL. [Table 1] summarizes some of the plants and phytochemicals that act as radioprotector against radio-genotoxicity in HPBL.
|Table 1: Preventive effects of some plants and phytochemicals against radio-genotoxicity in human lymphocytes|
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| > Conclusions and Future Directions|| |
Nowadays, several efforts are being made to reduce RT side effects. One of such tries is to apply the total radiation dose in fractions in order to preserve healthy tissues. Moreover, searches for new treatment methods to prevent radiation consequences are continuing, as well. Some of these researches are based on prevention from oxidative damage, as the major factor responsible for radiation-induced damage. Plants and phytochemicals as radioprotector were observed to diminish IR-induced DNA damage in HPBL at doses of 1–5 Gy.,,,,,,,,,,,,,,,,, Their effects are concentration-dependent and each of them presents an optimum radioprotective dose. Although, plants and phytochemicals mentioned in this review protect against IR-induced DNA damage in HPBL, clinical trials have not yet been undertaken with most of them. Two methods are suggested for preclinical plants and phytochemicals development as radioprotector. In the first method, comprehensive toxicological and pharmacological testing is performed to address the regulatory requirement for data on absorption, distribution, metabolism, excretion, and toxicity profiles before proceeding to the clinical investigation. In the second method, the radioprotective and radiosensitive effects are determined using both in vitro and in vivo testing in both normal tissues and tumors. If radiosensitive for tumor or absence of tumor protection and sufficient normal tissue protection is found, then the mechanism of action should be identified.
Finally, among plants and phytochemicals mentioned in this review, curcumin can be considered as a candidate for future studies in reduction of cancer patients' lymphocytopenia undergoing radiotherapy, because of its remarkable properties such as radioprotective for normal cells, radiosensitive for tumor cells, readily available, inexpensive, orally administered for human, does not have toxic implications in therapeutic dose range, can act through multiple mechanisms, easy handling and storage.
Financial support and sponsorship
Tehran University of Medical Sciences and Health Services grant number 28173.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Ghazali N, Shaw RJ, Rogers SN, Risk JM. Genomic determinants of normal tissue toxicity after radiotherapy for head and neck malignancy: a systematic review. Oral Oncol 2012;48:1090-100.
Groselj B, Sharma NL, Hamdy FC, Kerr M, Kiltie AE. Histone deacetylase inhibitors as radiosensitisers: effects on DNA damage signalling and repair. Br J Cancer 2013;108:748-54.
Jacobs GP. A review on the effects of ionizing radiation on blood and blood components. Radiat Phys Chem 1998;53:511-23.
Belloni P, Meschini R, Czene S, Harms-Ringdahl M, Palitti F. Studies on radiation-induced apoptosis in G0 human lymphocytes. Int J Radiat Biol 2005;81:587-99.
Wilkins RC, Kutzner BC, Truong M, Sanchez-Dardon J, McLean JR. Analysis of radiation-induced apoptosis in human lymphocytes: flow cytometry using Annexin V and propidium iodide versus the neutral comet assay. Cytometry 2002;48:14-9.
Blomgren H, Edsmyr F, Näslund I, Petrini B, Wasserman J. Distribution of lymphocyte subsets following radiation therapy directed to different body regions. Clin Oncol 1983;9:289-98.
Raben M, Walach N, Galili U, Schlesinger M. The effect of radiation therapy on lymphocyte subpopulations in cancer patients. Cancer 1976;37:1417-21.
Rotstein S, Blomgren H, Petrini B, Wasserman J, Baral E. Long term effects on the immune system following local radiation therapy for breast cancer. I. Cellular composition of the peripheral blood lymphocyte population. Int J Radiat Oncol Biol Phys 1985;11:921-5.
Heier HE. The influence of therapeutic irradiation of blood and peripheral lymph lymphocytes. Lymphology 1978;11:238-42.
Rand RJ, Jenkins DM, Bulmer R. T- and B-lymphocyte subpopulations following radiotherapy for invasive squamous cell carcinoma of the uterine cervix. Clin Exp Immunol 1978;33:159-65.
Gray WC, Chretien PB, Suter CM, Revie DR, Tomazic VT, Blanchard CL, et al.
Effects of radiation therapy on T-lymphocyte subpopulations in patients with head and neck cancer. Otolaryngol Head Neck Surg 1985;93:650-60.
Shirazi A, Mihandoost E, Mohseni M, Ghazi-Khansari M, Rabie Mahdavi S. Radio-protective effects of melatonin against irradiation-induced oxidative damage in rat peripheral blood. Phys Med 2013;29:65-74.
Shirazi A, Mihandoost E, Mahdavi SR, Mohseni M. Radio-protective role of antioxidant agents. Oncol Rev 2012;6:e16.
Mihandoost E, Shirazi A, Mahdavi SR, Aliasgharzadeh A. Can melatonin help us in radiation oncology treatments? Biomed Res Int 2014;2014:578137.
Arora R, Gupta D, Chawla R, Sagar R, Sharma A, Kumar R, et al.
Radioprotection by plant products: present status and future prospects. Phytother Res 2005;19:1-22.
Arora R. Herbal Radiomodulators: Applications in Medicine, Homeland Defence and Space. Wallingford: CABI Publishing; 2008.
Hutchinson F. Chemical changes induced in DNA by ionizing radiation. Prog Nucleic Acid Res Mol Biol 1985;32:115-54.
Shirazi A, Mihandoost E, Ghobadi G, Mohseni M, Ghazi-Khansari M. Evaluation of radio-protective effect of melatonin on whole body irradiation induced liver tissue damage. Cell J 2013;14:292-7.
Lavelle C, Foray N. Chromatin structure and radiation-induced DNA damage: from structural biology to radiobiology. Int J Biochem Cell Biol 2014;49:84-97.
Qiu GH. Protection of the genome and central protein-coding sequences by non-coding DNA against DNA damage from radiation. Mutat Res Rev Mutat Res 2015;764:108-17.
Close DM, Nelson WH, Bernhard WA. DNA damage by the direct effect of ionizing radiation: products produced by two sequential one-electron oxidations. J Phys Chem A 2013;117:12608-15.
Obe G, Pfeiffer P, Savage JR, Johannes C, Goedecke W, Jeppesen P, et al.
Chromosomal aberrations: formation, identification and distribution. Mutat Res 2002;504:17-36.
Dextraze ME, Gantchev T, Girouard S, Hunting D. DNA interstrand cross-links induced by ionizing radiation: an unsung lesion. Mutat Res 2010;704:101-7.
Martin LM, Marples B, Coffey M, Lawler M, Lynch TH, Hollywood D, et al.
DNA mismatch repair and the DNA damage response to ionizing radiation: making sense of apparently conflicting data. Cancer Treat Rev 2010;36:518-27.
Ward JF. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol 1988;35:95-125.
Goodhead DT. Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol 1994;65:7-17.
Jeggo P, Lavin MF. Cellular radiosensitivity: how much better do we understand it? Int J Radiat Biol 2009;85:1061-81.
Stojic L, Brun R, Jiricny J. Mismatch repair and DNA damage signalling. DNA Repair (Amst) 2004;3:1091-101.
Harms-Ringdahl M. Some aspects on radiation induced transmissible genomic instability. Mutat Res 1998;404:27-33.
Huang L, Snyder AR, Morgan WF. Radiation-induced genomic instability and its implications for radiation carcinogenesis. Oncogene 2003;22:5848-54.
Smith LE, Nagar S, Kim GJ, Morgan WF. Radiation-induced genomic instability: radiation quality and dose response. Health Phys 2003;85:23-9.
Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG. Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 1992;355:738-40.
Marder BA, Morgan WF. Delayed chromosomal instability induced by DNA damage. Mol Cell Biol 1993;13:6667-77.
Martins MB, Sabatier L, Ricoul M, Pinton A, Dutrillaux B. Specific chromosome instability induced by heavy ions: A step towards transformation of human fibroblasts? Mutat Res 1993;285:229-37.
Holmberg K, Fält S, Johansson A, Lambert B. Clonal chromosome aberrations and genomic instability in X-irradiated human T-lymphocyte cultures. Mutat Res 1993;286:321-30.
Limoli CL, Kaplan MI, Phillips JW, Adair GM, Morgan WF. Differential induction of chromosomal instability by DNA strand-breaking agents. Cancer Res 1997;57:4048-56.
Natarajan AT, Obe G, van Zeeland AA, Palitti F, Meijers M, Verdegaal-Immerzeel EA. Molecular mechanisms involved in the production of chromosomal aberrations. II. Utilization of Neurospora endonuclease for the study of aberration production by X-rays in G1 and G2 stages of the cell cycle. Mutat Res 1980;69:293-305.
Dolphin GW, Lloyd DC. The significance of radiation-induced chromosome abnormalities in radiological protection. J Med Genet 1974;11:181-9.
Vral A, Fenech M, Thierens H. The micronucleus assay as a biological dosimeter of in vivo
ionising radiation exposure. Mutagenesis 2011;26:7-11.
Rzeszowska-Wolny J, Polanska J, Pietrowska M, Palyvoda O, Jaworska J, Butkiewicz D, et al.
Influence of polymorphisms in DNA repair genes XPD, XRCC1 and MGMT on DNA damage induced by gamma radiation and its repair in lymphocytes in vitro
. Radiat Res 2005;164:132-40.
Inskip PD, Kleinerman RA, Stovall M, Cookfair DL, Hadjimichael O, Moloney WC, et al
. Leukemia, lymphoma, and multiple myeloma after pelvic radiotherapy for benign diseases. Radiat Res 1993;135:108-24.
Iwakawa M, Goto M, Noda S, Sagara M, Yamada S, Yamamoto N, et al.
DNA repair capacity measured by high throughput alkaline comet assays in EBV-transformed cell lines and peripheral blood cells from cancer patients and healthy volunteers. Mutat Res 2005;588:1-6.
Norppa H, Bonassi S, Hansteen IL, Hagmar L, Strömberg U, Rössner P, et al.
Chromosomal aberrations and SCEs as biomarkers of cancer risk. Mutat Res 2006;600:37-45.
Wojcik A, Gregoire E, Hayata I, Roy L, Sommer S, Stephan G, et al.
Cytogenetic damage in lymphocytes for the purpose of dose reconstruction: a review of three recent radiation accidents. Cytogenet Genome Res 2004;104:200-5.
International Atomic Energy Agency. Cytogenetic Analysis for Radiation Dose Assessment: A Manual. Technical Report Series No. 405, Vienna, Austria: IAEA; 2001. p. 105-22.
Bonassi S, Norppa H, Ceppi M, Strömberg U, Vermeulen R, Znaor A, et al
. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: Results from a pooled cohort study of 22 358 subjects in 11 countries. Carcinogenesis 2008;29:1178-83.
Miller GM, Kajioka EH, Andres ML, Gridley DS. Dose and timing of total-body irradiation mediate tumor progression and immunomodulation. Oncol Res 2002;13:9-18.
Yamazaki H, Yoshioka Y, Inoue T, Tanaka E, Nishikubo M, Sato T, et al.
Changes in natural killer cell activity by external radiotherapy and/or brachytherapy. Oncol Rep 2002;9:359-63.
Balmanoukian A, Ye X, Herman J, Laheru D, Grossman SA. The association between treatment related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas. Cancer Invest 2012;30:571-6.
Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, et al.
Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011;17:5473-80.
Lissoni P, Meregalli S, Bonetto E, Mancuso M, Brivio F, Colciago M, et al
. Radiotherapy-induced lymphocytopenia: Changes in total lymphocyte count and in lymphocyte subpopulations under pelvic irradiation in gynecologic neoplasms. J Biol Regul Homeost Agents 2005;19:153-8.
Howard JM, Chremos AN, Collen MJ, McArthur KE, Cherner JA, Maton PN, et al.
Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology 1985;88:1026-33.
Ghorbani M, Mozdarani H.In vitro
radioprotective effects of histamine H2 receptor antagonists against gamma-rays induced chromosomal aberrations in human lymphocytes. Iran J Radiat Res 2003;1:99-104.
Razzaghdoust A, Mozdarani H, Mofid B, Aghamiri SM, Heidari AH. Reduction in radiation-induced lymphocytopenia by famotidine in patients undergoing radiotherapy for prostate cancer. Prostate 2014;74:41-7.
Jagetia GC. Radioprotective potential of plants and herbs against the effects of ionizing radiation. J Clin Biochem Nutr 2007;40:74-81.
Hosseinimehr SJ. Trends in the development of radioprotective agents. Drug Discov Today 2007;12:794-805.
Patt HM, Tyree EB, Straube RL, Smith DE. Cysteine protection against X irradiation. Science 1949;110:213-4.
Shirazi A, Ghobadi G, Ghazi-Khansari M. A radiobiological review on melatonin: a novel radioprotector. J Radiat Res 2007;48:263-72.
Raviraj J, Bokkasam VK, Kumar VS, Reddy US, Suman V. Radiosensitizers, radioprotectors, and radiation mitigators. Indian J Dent Res 2014;25:83-90.
Yuhas JM, Spellman JM, Culo F. The role of WR-2721 in radiotherapy and/or chemotherapy. Cancer Clin Trials 1980;3:211-6.
Glover D, Riley L, Carmichael K, Spar B, Glick J, Kligerman MM, et al.
Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent). N Engl J Med 1983;309:1137-41.
Kligerman MM, Glover DJ, Turrisi AT, Norfleet AL, Yuhas JM, Coia LR, et al.
Toxicity of WR-2721 administered in single and multiple doses. Int J Radiat Oncol Biol Phys 1984;10:1773-6.
Gu J, Zhu S, Li X, Wu H, Li Y, Hua F. Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. PLoS One 2014;9:e95968.
Andreassen CN, Grau C, Lindegaard JC. Chemical radioprotection: a critical review of amifostine as a cytoprotector in radiotherapy. Semin Radiat Oncol 2003;13:62-72.
Nicolatou-Galitis O, Sarri T, Bowen J, Di Palma M, Kouloulias VE, Niscola P, et al.
Systematic review of amifostine for the management of oral mucositis in cancer patients. Support Care Cancer 2013;21:357-64.
Petrovska BB. Historical review of medicinal plants' usage. Pharmacogn Rev 2012;6:1-5.
Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009;7:65-74.
Sofowora A, Ogunbodede E, Onayade A. The role and place of medicinal plants in the strategies for disease prevention. Afr J Tradit Complement Altern Med 2013;10:210-29.
Dillard CJ, German JB. Phytochemicals: Nutraceuticals and human health. J Sci Food Agric 2000;80:1744-56.
Baliga MS, Rao S. Radioprotective potential of mint: a brief review. J Cancer Res Ther 2010;6:255-62.
Baliga MS, Rao S, Rai MP, D'souza P. Radio protective effects of the ayurvedic medicinal plant Ocimum sanctum
Linn. (Holy Basil): A memoir. J Cancer Res Ther 2015;12:91-107.
Pirayesh Islamian J, Mehrali H. Lycopene as a carotenoid provides radioprotectant and antioxidant effects by quenching radiation-induced free radical singlet oxygen: an overview. Cell J 2015;16:386-91.
Hosseinimehr SJ. Flavonoids and genomic instability induced by ionizing radiation. Drug Discov Today 2010;15:907-18.
Hosseinimehr SJ. Beneficial effects of natural products on cells during ionizing radiation. Rev Environ Health 2014;29:341-53.
Hanuman JB, Mishra AK, Sabata B. A natural phenolic lignin from Tinospora cordifolia
miers. J Chem Soc Perkin Trans 1986;7:1181-5.
Sharma P, Parmar J, Verma P, Goyal PK. Radiation induced oxidative stress and its toxicity in testes of mice and their prevention by Tinospora cordifolia
extract. J Reprod Health Med 2015;2:64-75.
Bertea CM, Azzolin CM, Doglia G. Identification of an EcoRI restriction site for a rapid and precise determination of beta-asarone-free Acorus calamus
cytotypes. Phytochemistry 2005;66:507-14.
Sandeep D, Nair CK. Protection from lethal and sub-lethal whole body exposures of mice to γ-radiation by Acorus calamus
L.: studies on tissue antioxidant status and cellular DNA damage. Exp Toxicol Pathol 2012;64:57-64.
Sandeep D, Nair CK. Protection of DNA and membrane from γ radiation induced damage by the extract of Acorus calamus
Linn: An in vitro
study. Environ Toxicol Pharmacol 2010;29:302-7.
Yasumasa I, Izumi M, Yutaka T. Abietane type diterpenoids from Salvia miltiorrhiza
. Phytochemistry 1989;28:3139-41.
Zhang Y, Guo J, Qi YH, Shao QJ, Liang J. The prevention of radiation-induced DNA damage and apoptosis in human intestinal epithelial cells by Salvianic acid A. J Radiat Res Appl Sci 2014;7:274-85.
Popov B, Georgieva S, Oblakova M, Bonev G. Effects of Haberlea
rhodopensis extract on antioxidation and lipid peroxidation in rabbits after exposure to 60Co-γ-rays. Arch Biol Sci Belgrade 2013;65:91-7.
Sangwan RS, Chaurasiya ND, Lal P, Misra L, Uniyal GC, Tuli R, et al.
Withanolide A biogeneration in in vitro
shoot cultures of ashwagandha (Withania somnifera
DUNAL), a main medicinal plant in Ayurveda. Chem Pharm Bull (Tokyo) 2007;55:1371-5.
Hosny Mansour H, Farouk Hafez H. Protective effect of Withania somnifera
against radiation-induced hepatotoxicity in rats. Ecotoxicol Environ Saf 2012;80:14-9.
Weiss JF, Landauer MR. Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology 2003;189:1-20.
Hazra B, Ghosh S, Kumar A, Pandey BN. The prospective role of plant products in radiotherapy of cancer: a current overview. Front Pharmacol 2012;2:94.
Hosseinimehr SJ, Mahmoudzadeh A, Ahmadi A, Mohamadifar S, Akhlaghpoor S. Radioprotective effects of hesperidin against genotoxicity induced by gamma-irradiation in human lymphocytes. Mutagenesis 2009;24:233-5.
Hosseinimehr SJ, Mahmoudzadeh A, Azadbakht M, Akhlaghpoor S. Radioprotective effects of Hawthorn
against genotoxicity induced by gamma irradiation in human blood lymphocytes. Radiat Environ Biophys 2009;48:95-8.
Hosseinimehr SJ, Mahmoudzadeh A, Ahmadi A, Ashrafi SA, Shafaghati N, Hedayati N. The radioprotective effect of Zataria multiflora
against genotoxicity induced by γirradiation in human blood lymphocytes. Cancer Biother Radiopharm 2011;26:325-9.
Devipriya N, Sudheer AR, Srinivasan M, Menon VP. Quercetin ameliorates gamma radiation-induced DNA damage and biochemical changes in human peripheral blood lymphocytes. Mutat Res 2008;654:1-7.
Srinivasan M, Devipriya N, Kalpana KB, Menon VP. Lycopene: An antioxidant and radioprotector against gamma-radiation-induced cellular damages in cultured human lymphocytes. Toxicology 2009;262:43-9.
Srinivasan M, Rajendra Prasad N, Menon VP. Protective effect of curcumin on gamma-radiation induced DNA damage and lipid peroxidation in cultured human lymphocytes. Mutat Res 2006;611:96-103.
Davari H, Haddad F, Moghimi A, Farhad Rahimi M, Ghavamnasiri MR. Study of radioprotective effect of green tea against gamma irradiation using micronucleus assay on binucleated human lymphocytes. Iran J Basic Med Sci 2012;15:1026-31.
Prasad NR, Srinivasan M, Pugalendi KV, Menon VP. Protective effect of ferulic acid on gamma-radiation-induced micronuclei, dicentric aberration and lipid peroxidation in human lymphocytes. Mutat Res 2006;603:129-34.
Garrido G, González D, Lemus Y, García D, Lodeiro L, Quintero G, et al. In vivo
and in vitro
anti-inflammatory activity of Mangifera indica
L. extract (VIMANG). Pharmacol Res 2004;50:143-9.
Rodeiro I, Delgado R, Garrido G. Effects of a Mangifera indica
L. stem bark extract and mangiferin on radiation-induced DNA damage in human lymphocytes and lymphoblastoid cells. Cell Prolif 2014;47:48-55.
Garg AK, Buchholz TA, Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal 2005;7:1630-47.
Jagetia GC. Radioprotection and radiosensitization by curcumin. Adv Exp Med Biol 2007;595:301-20.
Sebastia N, Montoro A, Montoro A, Almonacid M, Villaescusa JI, Cervera J, et al
. Assessment in vitro
of radioprotective efficacy of curcumin and resveratrol. Radiat Meas 2011;46:962-6.
Al Suhaibani ES. Protective effect of curcumin on gamma radiation-induced sister chromatid exchanges in human blood lymphocytes. Int J Low Radiat 2009;6:21-7.
Begum N, Prasad NR. Apigenin, a dietary antioxidant, modulates gamma-radiation-induced oxidative damages in human peripheral blood lymphocytes. Biomed Prev Nutr 2012;2:16-24.
Rithidech KN, Tungjai M, Whorton EB. Protective effect of apigenin on radiation-induced chromosomal damage in human lymphocytes. Mutat Res 2005;585:96-104.
Cavusoglu K, Yalcin E. Radioprotective effect of lycopene on chromosomal aberrations (CAs) induced by gamma radiation in human lymphocytes. J Environ Biol 2009;30:113-7.
Lee TK, Allison RR, O'Brien KF, Khazanie PG, Johnke RM, Brown R, et al.
Ginseng reduces the micronuclei yield in lymphocytes after irradiation. Mutat Res 2004;557:75-84.
Leskovac A, Joksic G, Jankovic T, Savikin K, Menkovic N. Radioprotective properties of the phytochemically characterized extracts of Crataegus monogyna,Cornus mas
and Gentianella austriaca
on human lymphocytes in vitro
. Planta Med 2007;73:1169-75.
Sebastià N, Almonacid M, Villaescusa JI, Cervera J, Such E, Silla MA, et al.
Radioprotective activity and cytogenetic effect of resveratrol in human lymphocytes: an in vitro
evaluation. Food Chem Toxicol 2013;51:391-5.
Kalpana KB, Devipriya N, Srinivasan M, Menon VP. Investigation of the radioprotective efficacy of hesperidin against gamma-radiation induced cellular damage in cultured human peripheral blood lymphocytes. Mutat Res 2009;676:54-61.
Cinkilic N, Cetintas SK, Zorlu T, Vatan O, Yilmaz D, Cavas T, et al.
Radioprotection by two phenolic compounds: chlorogenic and quinic acid, on X-ray induced DNA damage in human blood lymphocytes in vitro
. Food Chem Toxicol 2013;53:359-63.
Cinkilic N, Tüzün E, Çetintaş SK, Vatan Ö, Yılmaz D, Çavaş T, et al.
Radioprotective effect of cinnamic acid, a phenolic phytochemical, on genomic instability induced by X-rays in human blood lymphocytes in vitro
. Mutat Res Genet Toxicol Environ Mutagen 2014;770:72-9.
Dutta S, Gupta ML. Alleviation of radiation-induced genomic damage in human peripheral blood lymphocytes by active principles of Podophyllum hexandrum
: an in vitro
study using chromosomal and CBMN assay. Mutagenesis 2014;29:139-47.
Kanimozhi G1, Prasad NR, Ramachandran S, Pugalendi KV. Umbelliferone modulates gamma-radiation induced reactive oxygen species generation and subsequent oxidative damage in human blood lymphocytes. Eur J Pharmacol 2011;672:20-9.
Rao BN, Archana PR, Aithal BK, Rao BS. Protective effect of zingerone, a dietary compound against radiation induced genetic damage and apoptosis in human lymphocytes. Eur J Pharmacol 2011;657:59-66.
Shahani S, Rostamnezhad M, Ghaffari-Rad M, Ghasemi A, Pourfallah TA, Hosseinimehr SJ. Radioprotective effect of Achillea millefolium
L against genotoxicity induced by ionizing radiation in human normal lymphocytes. Dose Response 2015;13:1-5.