Magnetic hyperthermia therapy (MHT) involves heat generation using magnetic nanoparticles (MNPs) in response to an externally applied alternating current magnetic field. These MNPs can be specifically targeted to the tumor site for homogenous heating. Compared to MHT, conventional methods of HT cause heterogeneous heating of tumor and thus poor efficacy of cancer treatment. MHT has also been shown to effectively eliminate the highly chemo- and radio-resistant cancer stem cells in the tumor mass. Due to their diagnostic capability as well as heat-induced cancer cell killing ability, extensive research has been carried out to develop MNPs as potential cancer theranostic agent. The major focus of MNP research has been to design MNPs formulations for efficient targeting, increased colloidal stability, effective heat generation, and minimal inherent toxicity. A few recent MNPs formulations meet some of the required features and showed promising results in preclinical and clinical studies. HT applied through conventional modes has been combined with chemo- and radiotherapy, owing to its ability to increase oxygenation and drug supply due to vasodilation but has shown a limited success in clinic. However, a great hope has arisen from the MNPs to make combinatorial therapies more successful, not only because of the many advantages of MNPs mentioned but also due to their potential for targeted delivery of a range of anti-cancer drugs and radiosensitizing agents.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Ultraviolet radiation (UVR) is a very prominent environmental toxic agent. UVR has been implicated in the initiation and progression of photocarcinogenesis. UVR exposure elicits numerous cellular and molecular events which include the generation of inflammatory mediators, DNA damage, epigenetic modifications, and oxidative damages mediated activation of signaling pathways. UVR-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. UVR-induced carcinogenic mechanism has been well studied using various animal and cellular models. Human skin-derived dermal fibroblasts, epidermal keratinocytes, and melanocytes served as excellent cellular model systems for the understanding of UVR-mediated carcinogenic events. Apart from this, scientists developed reconstituted three-dimensional normal human skin equivalent models for the study of UVR signaling pathways. Moreover, hairless mice such as SKH-1, devoid of Hr gene, served as a valuable model for experimental carcinogenesis. Scientists have also used transgenic mice and dorsal portion shaved Swiss albino mice for UVR carcinogenesis studies. In this review, we have discussed the current progress in the study on ultraviolet B (UVB)-mediated carcinogenesis and outlined appropriate experimental models for both ultraviolet A- and UVB-mediated carcinogenesis.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Ultraviolet (UV) radiation is a very prominent environmental toxic agent. Particularly, UVB (280–320 nm – short wave) wavelength penetrates the epidermis and is completely absorbed in the upper dermis, whereas UVA (320–400 nm - long wave) penetrates to the deeper dermis. UVA is a relatively weak carcinogen than UVB because of its weak strength as a tumor initiating agent. UVB exposure elicits adverse effect which includes sunburn, basal and squamous cell carcinoma, melanoma, cataracts, photoaging of the skin and immunosuppression. Increased ozone depletion and modern lifestyle has increased the amount of UV exposure, and this consequently led to a surge in the incidence of skin cancer. UVB-irradiation acts as both tumor initiator and tumor promoter in animal models. UVB-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. Variety of cellular changes, which includes activation of transcription factors and protein kinases were altered during acute and chronic UVB-exposure. All these events leads to skin cancer development involving DNA damage, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant–defenses, and reactive oxygen species generation. An epidemiological study shows that human beings consuming varieties of vegetables and fruits are protected from UVB induced carcinogenesis. In the recent years, number of experimental evidences showed that natural nutraceuticals and phytoceuticals are vital targets for UVB-mediated cellular and molecular events and prevents cellular milieu from UVB mediated health effects. In this review, we have discussed the current progress in the study on UVB-mediated signaling that can be exploited as targets for phytochemicals.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Purpose: Valproic acid (VPA) is used mainly for the treatment of epilepsy and other seizure disorders, however, it is known to be one of histone deacetylase (HDAC) inhibitors. HDACIs have represented roles in radiation-sensitizing of cancer cells. This study is aimed to study to evaluate the radiosensitizing capability of VPA in MCF-7 breast cancer cell line. Materials and Methods: Cell viability and apoptosis were assayed using MTT and TUNEL assays, respectively and caspase-8 and caspase-9 activities were measured by commercially available kits. Results: Our finding showed that pre treatment of cells with VPA, notably enhanced apoptotic cell death in MCF-7 cell line. Our results showed that VPA sensitizes cancer cells against radiation. Conclusion: Valproic acid could be a beneficial radio-sensitizer in breast cancer radiotherapy.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

The comet assay (also known as single-cell gel electrophoresis) is a technique for the detection of DNA damage at the level of the individual cell. It is a versatile, relatively simple to perform and sensitive method. Although most investigations make use of its ability to measure DNA single-strand breaks, modifications to the method allow detection of cyclobutane pyrimidine dimers (CPDs), crosslinks, base damage, and apoptotic nuclei. Many investigators also interested in examining the DNA damage as a function of time after exposure to a known genotoxic agent. Here, we present a procedure of comet assay for the detection of DNA strand breaks, base damages, and CPDs that can be used to measure DNA damage during toxicity, oxidative stress, and ultraviolet radiation exposure and it can be applied in human toxicological biomonitoring scenarios.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Aim: Mammalian DNA Ligases play pivotal role in processes such as DNA replication, recombination, and repair, which qualifies them as potent therapeutic targets to eradicate cancer cells. Recently, we have identified a small molecule inhibitor, SCR7 and its oxidized form SCR7-pyrazine (2-mercapto-6,7-diphenylpteridin-4-ol) (SCR7-P), which can inhibit nonhomologous end-joining (NHEJ) in a Ligase IV-dependent manner. In the present study, we describe a water-soluble version of ligase inhibitor, sodium salt of SCR7-P (Na-SCR7-P) and its anti-tumor effects. Materials and Methods: Water soluble version of SCR7-P was synthesised. To study the inhibitory effect of Na-SCR7-P on ligases, we did in vitro DNA end joining assays using double strand DNA substrates. For this, different concentrations of Na-SCR7-P was used along with purified ligases or cell-free extracts. Further, cytotoxicity induced by Na-SCR7-P was evaluated through trypan blue exclusion assay, JC-1 assay and cell cycle analysis. Anti-tumor activity of Na-SCR7-P was investigated in Swiss albino mice and its off-target effects were studied by conducting kidney and liver test and histological evaluation. Further, the anti-angiogenic effect of the compound was studied using in ovo chorioallantoic membrane assay. Results: Na-SCR7-P inhibited NHEJ in a Ligase IV-dependent manner. However, unlike SCR7 and SCR7-P, it blocked joining catalyzed by all three ligases in vitro, making it an ideal cancer therapeutic agent, as it may target multiple DNA transaction processes within the cancer cells. Na-SCR7-P decreased mitochondrial membrane potential (MMP) leading to cell death in cancer cells. Importantly, the administration of Na-SCR7-P led to a significant reduction in tumor growth from 12^th day of treatment, and its impact was significantly higher than previously described SCR7, which targets Ligase IV within cells. Antitumor activity of Na-SCR7-P in mice resulted in enhanced lifespan, with minimal side effects. In addition, the in ovo chorioallantoic membrane assay revealed potent antiangiogenic property of Na-SCR7-P. Conclusion: Our results suggest that Na-SCR7-P can target NHEJ and other DNA repair pathways by disrupting Ligase mediated joining and can potentially be used as a strategy for cancer treatment, owing to its water solubility.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Failure in repair of DNA double-strand breaks (DSBs) could result in various disorders in mammals including cancer. Among various exogenous agents, radiation is one of the primary causes for induction of DSBs. Homologous recombination, nonhomologous end-joining, and a less efficient microhomology-mediated end-joining are responsible for repair of DSBs to ensure the genomic integrity and stability. This review highlights DNA damage response (DDR) induced following various insults to the genome and how the DNA repair mechanisms have evolved to restore genomic integrity. We also briefly discuss the potential therapeutic targets associated with DDR and DSB repair and novel inhibitors developed against such targets and their well-defined mechanism of action, which may increase sensitivity to traditional radio- and chemo-therapeutic modalities.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

The availability of safe and effective radiation countermeasures for the military and civilian population represents a significant unmet medical need. To expedite the development of countermeasures for life-threating situations, the United States Food and Drug Administration (US FDA) has implemented the “Animal Rule” which applies to the development and evaluation of drugs and biologics to reduce or prevent life-threatening conditions caused by exposure to lethal or permanently disabling agents where human efficacy trials are neither feasible nor ethical. In addition, the FDA has introduced several incentives (fast track, orphan drug status, and emergency use authorization [EUA]) to attract drug sponsors to develop such agents for human use. Repurposing is vital to make drugs available for life-threatening conditions. Drugs are commonly repurposed for new indications not originally envisioned. By repurposing a drug, it can be made available for human use much quicker, but this pathway also involves issues such as intellectual property rights as corporations are reluctant to expose their blockbuster pharmaceuticals to additional scientific scrutiny. Two radiomitigators for hematopoietic acute radiation syndrome (H-ARS) (Neupogen and Neulasta) have been approved by the FDA through repurposing. The EUA is a legal means for the FDA to approve new drugs or new indications for the previously approved drugs for use during a declared emergency and is a valid way to expedite drug development. Several promising agents with and without FDA investigational new drug (IND) status for ARS are under advanced development. In the next few years, we expect that the FDA will approve a few radioprotectors for H-ARS as well as gastrointestinal ARS via Animal Rule.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Aim: The present study was aimed to examine and evaluate the genotoxicity and cytotoxicity induced by different doses of cyclophosphamide (CP) in normal healthy cultured human peripheral blood lymphocytes. Materials and Methods: Genotoxicity and cytotoxicity was evaluated through mitotic index (MI), chromosomal aberrations, micronuclei frequency, and colony formation assay (plating efficiency [PE] and survival fraction), respectively. Results: It has been observed that CP (1, 2.5, and 5 μg/ml)) induced a dose-dependent increase in chromosomal aberrations and micronuclei frequencies in cultured human peripheral blood lymphocyte as compared to normal. A significant increase was observed in the percentage of aberrant cells and dicentrics/exchanges at 1 and 2.5 μg/ml CP and aberrant cells, breaks, fragments, and dicentrics/exchanges at 5/μg/ml CP. A dose-dependent decrease in values of MI and nuclear division index was also observed in CP-treated group. The frequency of micronuclei in binucleated cells showed a dose-dependent increase. In colony formation assay, PE and surviving fraction values showed significant (P < 0.001) and dose-dependent decrease in the CP treatment groups. Conclusion: The results of present study suggest that CP has genotoxic and cytotoxic effect on cultured human lymphocytes.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

One of the most frequently applied bioelectromagnetic effects is the deep heating of living species with electromotive force energy. Despite its long history, hyperthermia is a rarely applied oncotherapy because of controversial results and complicated control. The challenge in clinical studies of oncological hyperthermia is the disharmony of the local response and local control with overall survival. Both whole-body (complete isothermia for the body) and local (isothermia for the chosen target) heating show excellent local effects; however, this is not followed with the expected elongation of survival time. A possible solution could be nonisothermal heating to the heterogeneity of the malignancy itself. The distinguishing parameters to select the target are the electromagnetic properties of the malignant tissue together with the physiological differences between malignant cells and their healthy counterparts. Selection could allow for cellular targeting, generating natural reactions, such as programmed cell death (apoptosis) followed by immunogenic cell death involving extended immune reactions. This complex method is a new kind of hyperthermia, named modulated electrohyperthermia (tradename oncothermia). The selective, nonequilibrium energy absorption is well synergized with modern radiation therapies, presenting a solution of an active and controllable tumor-specific immune reaction and subsequent abscopal effects.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Metastasis or cancer is a functional, molecular and structural disorder which has been an unsolved and fatal mystery and leads to death in most of the individuals suffering from it in spite of the advances made in biomedical and oncological fields. Structurally a tissue consists of cells enclosed by glycocalyx (partially or completely), extracellular matrix incorporating lymphatic and mircovessels. There is a specific amount of glycocalyx sandwiched between extracellular cell matrix and cell membrane depending on the type of the tissue and cell and their location in the biosystems. The common constituents of glycocalyx include biomolecules such as glycolipids, glycoproteins, and oligosaccharides; the glycoproteins are trans-membrane proteins. Any impact due to the interaction between inter- and/or intra-cellular biomolecules or any expected xenobiotics affect extracellular matrix, glycocalyx, cell membrane, cell organelles; these are the prime targets for the investigation related to metastasis. Somehow or the other the glycocalyx has attracted relative less attention of the researchers. The various aspects of the prometastatic interactions involve ligand-receptors, integrins, and other cellular receptors; glycocalyx has its role in such interactions. There are changes in the physicochemical parameters of glycocalyx which affect the cell membrane adversely. These result in malfunctioning of cell signaling, cell proliferation, cell migration, etc. There have been relatively less reports on the structural and functional changes in glycocalyx specifically related to circulating tumor cells and the cancerous cells of organs such as ovary, breast tissue, lungs, and hepatic tissues. In this presentation, an effort is made to review and evaluate the changes in glycocalyx during such interactions between the glycocalyx and the prometastatic molecules.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Context: The study of photon interactions with biological materials is essential in radiation medicine and biology, nuclear technology and space research, since radioactive sources are used. Aims: A study of mass attenuation coefficient, effective atomic numbers (Z_eff) and electron density of some commonly used skeletal muscle relaxants. Materials and Methods: We have measured the mass attenuation some commonly used skeletal muscle relaxants such as tubocurarine chloride, gallamine triethiodide, pancuronium bromide, suxamethonium bromide and mephenesin for various gamma sources of energy ranging from 84keV to 1330 keV (¹⁷⁰Tm, ⁵⁷Co, ¹⁴¹Ce, ²⁰³Hg, ⁵¹Cr, ¹¹³Sn, ²²Na, ¹³⁷Cs, ⁶⁰Co, ²²Na and ⁶⁰Co). The measured values agree with the theoretical values. The effective atomic numbers (Z_eff) and electron density (N_e) of commonly used skeletal muscle relaxants for total and coherent, incoherent, photoelectric absorption, pair production in atomic and nuclear field photon interaction have been computed in the wide region 1keV to 100GeV using an accurate database of photon-interaction cross sections and the WinXCom program. Results: The significant variation of Zeff and Nel is due to the variations in the dominance of different interaction process in different energy regions. A comparison is also made with the single values of the Zeff and Nel provided by the program XMuDat. We have also calculated CT numbers, kerma values relative to air and dose rate for relaxants which are also not remaining constant with energy. Conclusions: The computed data of mass attenuation coefficient, effective atomic numbers (Z_eff) and electron density and CT numbers in the low energy region helps in visualizing the image of the biological samples and precise accuracy in treating the inhomogenity of them in medical radiology. The calculated kerma values relative to air and dose rate for relaxants are useful in radiation medicine.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive type of non-Hodgkin's lymphoma that accounts for ~40% of all lymphomas. DLBCL is considered to be clinically heterogeneous with highest mortality rate. Recent advances in gene expression profiling helped in identifying different subtypes of DLBCL, and since then, many therapeutic options have been explored to treat DLBCL patients. Although it is effective, a significant proportion of the patients suffer due to drug resistance. One of the potential causes for this could be elevated DNA repair in the resistant cancer cells. Thus, the present study is aimed at investigating the potential of SCR7, a DNA repair inhibitor in inducing cytotoxicity on a DLBCL cell line, and to study its ability to potentiate effect when used in combination with ionizing radiation. Materials and Methods: DLBCL cell line, Standford University Diffuse Histiocytic Lymphoma 8 (SUDHL8) was treated with various concentrations of SCR7, a DNA repair inhibitor that targets nonhomologous DNA end joining. While cytotoxicity induced by SCR7 was evaluated through trypan blue assay and flow cytometry analysis, 5,5',6,6 tetrachloro-1,1',3,3'-tetraethyl benzimidazol-carbocyanine iodide and annexin V-FITC/propidium iodide [PI] double-staining assays were used to study the mechanism of cell death. Modulation in the level of DNA repair and apoptotic proteins following treatment with SCR7 was examined by immunoblotting. Effect of SCR7 on sensitizing radiotherapy was further investigated in the SUDHL8 cells. Results: SCR7 induced cytotoxicity in the DLBCL cell line in a concentration- and time-dependent manner. Cell cycle analysis and annexin V/PI double-staining assay confirmed apoptosis in cells without interfering with cell cycle progression. Change in mitochondrial membrane potential in conjunction with alterations in the levels of apoptotic proteins suggested activation of both intrinsic and extrinsic pathways of apoptosis. Importantly, administration of SCR7 potentiated the effect of radiation upon combination therapy in DLBCL. Conclusion: Our results suggest that SCR7 could be developed as an alternative chemotherapeutic approach against DLBCL and is also effective along with radiotherapy.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Superparamagnetic particles (SUPs) have been used in many applications in the area of hyperthermia-based cancer treatment, as a magnetic resonance imaging contrast agent, as a carrier for drug, in the removal of toxic ions, etc. When SUPs are dispersed in liquid, they can experience Brownian motion and Néel's spin relaxations. In the presence of direct current magnetic field, SUPs do not show a hysteresis loop. Because of this, they are unable to produce heat. However, in alternating current magnetic field (AMF) of a few kHz and small magnetic fields, they can generate heat. For the treatment of cancer, hyperthermia temperature of 43°C is required, at which temperature cancer cells can be killed selectively, but normal cells can survive. The theory behind heat generation from SUPs in the presence of AMF will be discussed in this work.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

The possible detonation of a radiological dispersal device or improvised nuclear device in a metropolitan city, or the accidental exposures to a radiation source, nuclear accidents, or the all-to-often threats of radiological/nuclear terrorism have led to the urgent need to develop essential analytic tools to assess such radiation exposures, especially radiation doses to exposed individuals. This exposure-assessing work using biological samples, and discipline, is known as biodosimetry. As of late, this field has progressed significantly as it has made use of the advances within newer areas of biologic analytics, namely omics (genomics, proteomics, metabolomics, and transcriptomics), lymphocyte kinetics, optically stimulated luminescence, and electron paramagnetic resonance technology in addition to conventional cytogenetic techniques. The use of automated high throughput platforms and the planning for laboratory surge capacity during the time of need are the latest developments in the field of biomarkers for biodosimetry. Such biomarkers are also needed for radiation exposure/dose conversion estimates that are essential for the development and application of radiation countermeasures, from animals to humans and that are currently being developed following the US Food and Drug Administration Animal Rule. Here, we present and discuss the current status of various biomarkers for assessing radiation dose after radiation exposure. It is anticipated that with the advent of improved biomarkers and associated biomarker platforms for the acute radiation syndrome, exposed victims can be more efficiently triaged and appropriately treated than is currently allowable. The latest advances in the field, and identify the areas where improvement is needed are also listed and discussed.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Objective: Direct exposure of the nucleus to radiation, is the primary cause of various radiobiological effects. However, the cytoplasm is equally exposed to radiation during treatments that result in activation of intracellular response. Thus, the present study is aimed at investigating (1) whether cytoplasmic irradiation affects double-strand breaks (DSBs) repair when the cytoplasm (C) and nucleus (N) is irradiated sequentially, and (2) whether the cytoplasmic irradiation alone is sufficient to induce DNA DSBs in the nucleus. Materials and Methods: To distinguish the radiobiological effects between nuclear and cytoplasmic irradiation, all the experiments were conducted using the SPICE - National Institute of Radiological Sciences microbeam (SPICE) that can target precisely the N and/or C with desired number of 3.4 MeV protons. We examined the kinetics of DSB repair in WI-38 normal human fibroblast cells that were irradiated by microbeam targeted to the N, C, or N + C. Cells were fixed at various time points between 1 and 24 h postirradiation. Subsequently, they were immunostained with antibodies against γ-H2AX, a DSB marker, and imaged, to quantify the residual DSB in each nucleus. Results: Microbeam irradiation induced significant γ-H2AX, directly proportional to the number of protons delivered per N. In the C-targeted cells, γ-H2AX levels did not increase significantly, compared to controls, 1-h postirradiation. However, 4-h postirradiation, γ-H2AX levels were significantly increased in C-targeted cells, compared to nonirradiated controls, and the increase was proportional to the number of protons delivered. Cells irradiated with 500 protons per N, showed lowered residual γ-H2AX levels in N + C cells additionally irradiated with 500 or 1000 protons targeted to the C, 16 and 24 h postirradiation, respectively. Conclusion: Our results suggest that cytoplasmic damage triggers enhanced repair of DSBs that are induced on nucleus irradiation.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Introduction: Curcumin, a component of the spice turmeric has widely reported anticancer properties in several types of cancer. The differential accumulation and mechanism of its action in normal and cancer cells have proven its potential in targeting tumor. Therefore, it was of interest to label curcumin with a suitable radionuclide and explore its potential for use in nuclear medicine. Materials and Methods: Curcumin was labeled with ¹²⁵I by iodogen method. The radiochemical purity was analyzed by paper electrophoresis and high-performance liquid chromatography (HPLC) method. Cell binding was carried out in murine lymphoma and melanoma cell lines. Bioevaluation and pharmacokinetics of radioiodinated curcumin was carried out in lymphoma-bearing mice for various time points (1, 3, 24, and 48 h). Results: The efficiency of labeling was >75% and the radiochemical purity postpurification was >95% The maximum uptake (~7% at 2 h, 37°C using 5 × 10⁵ cells) was observed in EL4 cells. Significant tumor uptake in lymphoma-bearing mice was observed at 180 min (3.3 ± 0.76% ID/g). In addition, pharmacokinetics of radioiodinated curcumin is fast, with the majority of the preparation out of the bloodstream in 3 h. Conclusion: The results of these studies suggest that curcumin has the potential for targeting lymphomas, which may be used as diagnostic/therapeutic agent by labeling with other radionuclides.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

[FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Objective: Wide-scale cell death, following chemo and radiation therapy, is a major concern in clinical therapy of cancer. The need to identify agents with a potential for chemo and radioprotective potential has assumed great importance. The study aims at the evaluation of the efficacy of picroliv, a potent antioxidant derived from the plant Picrorhiza kurroa, as cyto- and radioprotector. Materials and Methods: Picroliv was fed to mice in a dose of 20 and 30 mg/kg, i.p. daily for 15 days following 4 Gy gamma rays exposure. Body weight, mortality, and hematology were assessed along with endogenous spleen colony-forming unit (CFU) and micronucleus (MN) scoring. In vitro cytoprotective activity was assessed on Allium cepa root meristem growth parameters against cyclophosphamide-induced genotoxicity by determination of mitotic index (MI) and chromosome aberrations (CA). Results: Picroliv treatment resulted in reduced body weight loss, recovery of hematological parameters, increased CFU preservation, and reduced MN expression. Picroliv caused an increase in root length and number of A. cepa simultaneously exposed with cyclophosphamide. Cyclophosphamide-induced cellular damage as measured by MI, and CA was significantly less. Picroliv at 10 mg/ml concentration showed normal dividing cells with few fragments, and sticky chromosome reversing the severe cytotoxicity of cyclophosphamide expressed with chromosome fragmentation, vagrant, sticky, and C-anaphase chromosomes. Conclusion: The results of this study strongly suggest picroliv to be a promising agent for ameliorating injury, following radiation and chemotherapy. The potent antioxidant, hepatoprotective, and immune-modulatory properties of picroliv may be responsible for the apparent cyto- and radioprotective activity.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Radiation carcinogenesis may be associated with external and/or internal sources of radiation exposure during accidental, occupational, or diagnostic/therapeutic conditions. Most of the radiation carcinogenic events are established after acute doses of low linear energy transfer external radiation. Moreover, the carcinogenic effects of internalized radioisotopes are also reported at their acute/chronic doses. In this regard, actinide radionuclides (like 238U, 239Pu, 232Th, and 241Am) are of great importance as fuel material or waste generated during nuclear power production. These radionuclides may result in incidence of cancer when internalized at high doses while accidental or occupation exposure. Even though the basic carcinogenic mechanism after external or internal radiation exposure remains the same, the magnitude of systemic or target specific radiation effects may vary in these radiation exposure conditions. The majority of the studies investigating biological, carcinogenic, and other health effects of actinide radionuclides are limited only up to quantification of these effects without much mechanistic insights. Moreover, the radiobiological processes, such as bystander effect, genomic instability, and adaptive response, governing the cellular radiosensitivity of targeted/nontargeted cells also need to be studied in the context of carcinogenesis after actinide radionuclides internalization. The review aims to highlight the emerging radiobiological concepts and missing links about actinide radionuclides-induced carcinogenesis. In addition, an overview has been presented about biological and health effects of major actinide radionuclides.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Exposure of cells to ionizing radiation causes generation of intracellular reactive oxygen species (ROS) which are implicated in the mechanism of carcinogenesis. Molecular steps involved in the transformation of normal cells to cancer cells have been enigmatic but generally believed to arise from aberration in cellular redox homeostasis. In normal cell function, a delicate balance is maintained between ROS generated in the metabolic process and level of endogenous antioxidant defense. ROS are known to regulate various cellular functions, such as cell division, signal transduction, and apoptosis. Cells experience oxidative stress when excess production of ROS occurs inside a cell upon exposure to external stressor agents. This redox imbalance affects the cellular functions due to DNA strand breaks, chromosomal aberrations, gene mutations, alteration in signal transduction, and inhibition of apoptosis leading to induction of cancer and other diseases. Radiation-induced ROS are involved in initiation and promotion of carcinogenesis. Therefore, detoxification of ROS by exogenous antioxidants including dietary polyphenols offers an important strategy for cancer prevention. Recent research results have shown that resistance of cancer stem cells to therapies is linked to low level of ROS. Interestingly, in vitro and in vivo experiments have reported that radiotherapy- and chemotherapy-induced ROS in cytosol sensitize the tumor cells to death, resulting in tumor growth retardation. This review is an attempt to delineate mechanisms of ROS in carcinogenesis and prevention by dietary compounds. Natural polyphenols and dietary antioxidants hold potential to prevent cancer. Interventions in ROS-mediated signal alteration, apoptosis activation, and modulation of epigenetic processes may offer effective cancer prevention strategy.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Cancer causes millions of deaths each year globally. In most patients, the cause of treatment failure is found associated with the resistance to chemotherapy and radiotherapy. The development of tumor cell resistance evokes multiple intracellular molecular pathways. In addition, the limitation in treatment outcome arises due to unintended cytotoxic effects of the synthetic anticancer drugs to normal cells and tissues. Considerable focus of research is, therefore, devoted to examine plant-based herbal compounds which may prove potential anticancer drug for developing effective cancer therapy. Research results from our laboratory have shown that ellagic acid (EA), a natural flavonoid displays enhanced tumor toxicity in combination with gamma radiation to many types of cancers in vitro as well as in vivo. Studies on the underlying mechanisms of toxicity suggest that EA employs the cellular signaling pathways in producing the observed effects. This paper gives an account of molecular mechanisms of EA-induced apoptosis process in tumor cytotoxicity. It is suggested that EA acts as a novel radiosensitizer for tumors and a radioprotector for normal cells which may offer a novel protocol for cancer treatment.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Parental exposure of mice to radiation and chemicals causes a variety of adverse effects in the progeny, and the tumor-susceptibility phenotype is transmissible beyond the first postradiation generation. The induced rates of tumors were 100-fold higher than those known for mouse specific locus mutations. There were clear strain differences in the types of naturally-occurring and induced tumors and most of the latter were malignant. Another important finding was that germ-line exposure elicited very weak tumorigenic responses, but caused persistent hypersensitivity in the offspring for the subsequent development of cancer by the postnatal environment. Various disorders were induced in the offspring of mice exposed to radiation. Microsatellite mutations increase dose-dependently and accumulated for 58 generations in the offspring of male parental mice exposed to single dose of X-rays. Changes in gene expression also transmitted to further generations. Radiation-induced genomic instability in germ cells may enhance cancer and other disorders in next generation. In humans, a higher risk of leukemia and birth defects has been reported in the children of fathers who had been exposed to radionuclides in the nuclear reprocessing plants and to diagnostic radiation. These findings have not been supported in the children of atomic bomb survivors in Hiroshima and Nagasaki, who were exposed to higher doses of atomic radiation. However, long-term monitoring of children by Russian Federation Children's Center of Antiradiation Protection after Chernobyl accident shows higher prevalence of malignant neoplasm, mostly childhood cancer, malformation, and other disorders in the children of residents exposed to contaminated radionuclides (>556 kBq/m²). Persistent accumulation of genomic instability may cause various disorders in a further generation in human. This view will gain support from our mouse experiments, because the induced rate of solid tumors in the offspring of mice exposed to radiation is much higher than that of leukemia.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Increase in radionuclide application has gone far and wide in the last many decades; though its usage has benefited the society at large, however occasional unplanned exposure to radiation (terrorist/accidental) has also troubled human life. Exposure of humankind to nuclear disaster, accidental and natural background radiation exposure, has created the need to develop complete understanding of the subject and preparedness for having safe countermeasures. In whole-body radiation exposure scenario, all the three organs are responsible for leading the animal to its death; however, hematopoietic (HP) organ is the first to collapse followed by gastrointestinal (GI) and respiratory systems. Radiation-induced basic damage in these organs follows more or less similar pattern. Derangement starts with radiation-induced reactive oxygen species causing damage to DNA, lipids, and proteins and disturbing their regulatory pathways. However, damage in HP and GI is more rapid and severe due to the presence of highly radiosensitive multipotent stem cells essential to meet the need of high cell turnover rate in these organs. To overcome radiation-induced damage to these vital organs, serious efforts are continued globally to find safe remedial measure.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]

Adverse radiation effect (ARE) in the brain is the reactive inflammation, vasculitis, and necrosis that occurs as a complication of radiotherapy. There are two main categories of ARE that result in vasogenic cerebral edema: first, a residual irritant mass of the targeted lesion; and second, radiation-damaged perilesional normal brain tissue in a reactive state. Radiation injury leads to fibrinoid and coagulative necrosis of different cell types and fibrinoid necrosis and hyalinization of vessels. The clinical consequence of ARE is neurologic impairment secondary to vasogenic edema in the normal brain. Neuroimaging may aid in differentiating tumor recurrence from ARE. However, imaging studies are not definitive, and their utility in this setting remains controversial. The management of patients with ARE is dictated by symptom occurrence. The definitive management of symptomatic ARE is craniotomy and resection. Alternative therapies include bevacizumab, laser-interstitial thermal therapy, and reirradiation.

[ABSTRACT]  [FULL TEXT]  [PDF]  [Mobile Full text]  [EPub] [CITATIONS]