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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radiation therapy is a primary treatment modality for brain tumors, yet it has been linked to the increased incidence of secondary, post-radiation therapy cancers. These cancers are thought to be linked to indirect radiation-induced bystander effect. Bystander effect occurs when irradiated cells communicate damage to nearby, non-irradiated 'bystander' cells, ultimately contributing to genome destabilization in the non-exposed cells. Recent evidence suggests that bystander effect may be epigenetic in nature; however, characterization of epigenetic mechanisms involved in bystander effect generation and its long-term persistence has yet to be defined. To investigate the possibility that localized X-ray irradiation induces persistent bystander effects in distant tissue, we monitored the induction of epigenetic changes (i.e. alterations in DNA methylation, histone methylation and microRNA (miRNA) expression) in the rat spleen tissue 24 h and 7 months after localized cranial exposure to 20 Gy of X-rays. We found that localized cranial radiation exposure led to the induction of bystander effect in lead-shielded, distant spleen tissue. Specifically, this exposure caused the profound epigenetic dysregulation in the bystander spleen tissue that manifested as a significant loss of global DNA methylation, alterations in methylation of long interspersed nucleotide element-1 (LINE-1) retrotransposable elements and down-regulation of DNA methyltransferases and methyl-binding protein methyl CpG binding protein 2 (MeCP2). Further, irradiation significantly altered expression of miR-194, a miRNA putatively targeting both DNA methyltransferase-3a and MeCP2. This study is the first to report conclusive evidence of the long-term persistence of bystander effects in radiation carcinogenesis target organ (spleen) upon localized distant exposure using the doses comparable with those used for clinical brain tumor treatments.
Carcinogenesis 2007 Aug
PMID:Role of epigenetic effectors in maintenance of the long-term persistent bystander effect in spleen in vivo. 1734 36

Poly(ADP-ribose) polymerases (PARP) is enzyme family repairing single or double DNA strand breaks induced by different alkylating agents, ionizing- or UV-irradiation as well as by oxidative stress. Poly(ADP-ribose) polymerase-1 (PARP-1) is the most studied enzyme involved in a number of pathways including DNA replication and repair, recombination, gene transcription, cell proliferation and death. A positive correlation between the PARP-activity and the life span of different mammalians has been detected. PARP inhibition in vitro with inhibitors of PARP activity (3-aminobenzamide, nicotinamide, picolinamide e.t.c.) in cells from wild type or PARP-1(-/-) mice was followed by high genomic instability (i.e. aneuploidy, gene amplifications and deletions, micronuclei formation, sister chromatic exchange, cell ploidy and centrosome number increase) and increased sensitivity to mutagens. Life span reduction, latency period of spontaneous tumors development shortening and the increase in susceptibility to carcinogens have been observed in PARP-knockout mice. Treatment with PARP inhibitors stimulated chemical and radiation carcinogenesis in animals. The PARP-1(-/-) mice being additionally disrupted in WRN, p53, DNA-PKcs or Ku80 genes the promotion of spontaneous carcinogenesis was observed as compared with a single gene-disrupted mice. Available data suggest a significant role of PARP in maintenance of genomic stability, preventing of aging and carcinogenesis.
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PMID:[Poly(ADP-ribosa)polymerase--the relationships with life span and carcinogenesis]. 1830 94

In order to elucidate the involvement of metallothionein (MT) in radiation carcinogenesis, we examined the susceptibility of MT-I/II null mice to carcinogenesis and oxidative DNA damage resulting from X-irradiation. Eight-week-old female MT-I/II null mice and wild-type mice were exposed to whole-body X-irradiation at doses of 1.0, 1.5 or 2.0 Gy once a week for 6 weeks. Incidence of thymic lymphoma was determined at 24 weeks after the first exposure to X-irradiation. The frequency of thymic lymphomas induced by X-irradiation (at 1.5 and 2.0 Gy) was significantly higher in MT-I/II null mice than in wild-type mice. In addition, although the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were increased in the serum and urine of both strains of mice 24 hr after exposure to a single bout of whole body X-irradiation, these increases were significantly greater in the MT-I/II null mice than in the wild-type mice. Thus, the present results suggest that MT plays a protective role against carcinogenesis and oxidative DNA damage caused by X-irradiation.
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PMID:Role of metallothionein as a protective factor against radiation carcinogenesis. 1904 87

The biological effects of radiation result primarily from damage to DNA. There are three effects of concern to the radiologist that determine the need for radiation protection and the dose principle of ALARA (As Low As Reasonably Achievable). (1) Heritable effects. These were thought to be most important in the 1950s, but concern has declined in recent years. The current ICRP risk estimate is very small at 0.2%/Sv. (2) Effects on the developing embryo and fetus include weight retardation, congenital anomalies, microcephaly and mental retardation. During the sensitive period of 8 to 15 weeks of gestation, the risk estimate for mental retardation is very high at 40%/Sv, but because it is a deterministic effect, there is likely to be a threshold of about 200 mSv. (3) Carcinogenesis is considered to be the most important consequence of low doses of radiation, with a risk of fatal cancer of about 5%/Sv, and is therefore of most concern in radiology. Our knowledge of radiation carcinogenesis comes principally from the 60-year study of the A-bomb survivors. The use of radiation for diagnostic purposes has increased dramatically in recent years. The annual collective population dose has increased by 750% since 1980 to 930,000 person Sv. One of the principal reasons is the burgeoning use of CT scans. In 2006, more than 60 million CT scans were performed in the U.S., with about 6 million of them in children. As a rule of thumb, an abdominal CT scan in a 1-year-old child results in a life-time mortality risk of about one in a thousand. While the risk to the individual is small and acceptable when the scan is clinically justified, even a small risk when multiplied by an increasingly large number is likely to produce a significant public health concern. It is for this reason that every effort should be made to reduce the doses associated with procedures such as CT scans, particularly in children, in the spirit of ALARA.
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PMID:Radiation biology for pediatric radiologists. 1908 23

Cancer prevention has to be based on robust biological and epidemiological data, therefore its reappraisal becomes mandatory in view of recent progress in the understanding of carcinogenesis. The first phase of the carcinogenic process, that of initiation, is generally associated with mutation; however the role of extrinsic mutagens is less critical than was thought two decades ago. During intracellular oxygen metabolism, reactive oxygen species (ROS) are made which are potent mutagens. Defense mechanisms against these intrinsic mutagens include scavenger and enzymatic systems which destroy them (catalase, superoxide dismutase). When the radiation dose is low, DNA repair is very effective as well as the elimination of cells with unrepaired or misrepaired DNA. Therefore a small increase in the number of ROS, such as that caused by a small dose of radiation has most probably no significant effect on the risk of DNA damage. These conclusions are consistent with the concept of a practical threshold. The second phase, that of promotion, appears to be the key one. During the promotion phase, initiated cells must acquire new properties (immortalization, release of angiogenic factors, resistance to hypoxia, etc.) in order to become precancerous. This evolution is due to the accumulation in the genome of 6 to 10 new alteration defects. In the clone of initiated cells, the occurrence in one cell of a mutation or an epigenetic event gives birth to a subclone. There is a Darwinian type competition between the subclones and those with the more rapid growth because dominant (the acceleration of the growth rate can be due to shorter cell cycles or to an alleviation of cell proliferation exerted by the neighboring cells or the microenvironment). In the dominant subclones new genomic events provoke the appearance of new subclones growing more rapidly and having greater autonomy. The process is very slow because the specific genetic events that favour this evolution seldom occur. Promoting factors are agents that either perturb intercellular signalling or stimulate cell proliferation (e.g. hormones) or increase cell mortality: mechanical or chemical irritation (e.g. alcohol, bacteria, viruses) thereby inducing compensatory cell proliferation. Thus, gradually precancerous cells become able to divide more rapidly with greater autonomy. This phase ends when a subclone of cells has acquired the capacity of autonomous proliferation. The third phase is that of progression during which cells proliferate regularly without any stimulation. In one of the cells of one of the precancerous lesions (e.g. polyps) a cell acquires the capacity of invading surrounding tissue or to metastasize. The whole carcinogenic process is very slow, extending over several decades, because the specific mutations seldom occur and the probability of an accumulation of several specific mutations in the same cell or cell lineage is very small. It can be accelerated by intense stimulation of cell proliferation or genetic instability. Ionizing radiations act firstly as a mutagen, however when the dose is high they also kill a significant proportion of cells and by a homeostatic mechanism they induce cell proliferation and clonal amplification. It has been claimed that even the smallest dose of radiation can induce a cancer. This concept is associated with the LNT model and it is not based on scientific evidence. It has fuelled a fear of radiation which had detrimental consequences. Conversely the high efficacy of defense mechanisms against radiocarcinogenesis, particularly when the tissue is not disorganized, can explain the lack of carcinogenic effect of contamination by small doses of radium or thorium which has been observed on radium dial painters or in patients injected with thorotrast. The study of second cancers in patients treated by radiotherapy could provide important information and should be actively pursued with two aims: reduce the incidence of second cancers; to better understand radiocarcinogenesis and the relation between dose and carcinogenic effect.
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PMID:[Prevention of cancer and the dose-effect relationship: the carcinogenic effects of ionizing radiations]. 1953 15

The intra-S checkpoint response to 254 nm light (UVC)-induced DNA damage appears to have dual functions to slow the rate of DNA synthesis and stabilize replication forks that become stalled at sites of UVC-induced photoproducts in DNA. These functions should provide more time for repair of damaged DNA before its replication and thereby reduce the frequencies of mutations and chromosomal aberrations in surviving cells. This review tries to summarize the history of discovery of the checkpoint, the current state of understanding of the biological features of intra-S checkpoint signaling and its mechanisms of action with a focus primarily on intra-S checkpoint responses in human cells. The differences in the intra-S checkpoint responses to UVC and ionizing radiation-induced DNA damage are emphasized. Evidence that [6-4]pyrimidine-pyrimidone photoproducts in DNA trigger the response is discussed and the relationships between cellular responses to UVC and the molecular dose of UVC-induced DNA damage are briefly summarized. The role of the intra-S checkpoint response in protecting against solar radiation carcinogenesis remains to be determined.
Carcinogenesis 2010 May
PMID:The human intra-S checkpoint response to UVC-induced DNA damage. 1979 1

Health risks from exposure to high doses of ionizing radiation are well characterized from epidemiological studies. Uncertainty and controversy remain for extension of these risks to the low doses and low dose rates of particular relevance in the workplace, in medical diagnostics and screening, and from background radiations. In order to make such extrapolations, a number of concepts have been developed for radiation protection, partly on the basis of assumed processes in the mechanisms of radiation carcinogenesis. Included amongst these are the assumptions of a linear no-threshold dose response and simple scaling factors for dose rate and radiation quality. With a progressive reduction in recommended dose limits over the past half century, these approaches have had considerable success in protecting humans. But do they go far enough or, conversely, are they overprotective? Four selected underlying aspects are considered. It is concluded that (1) even the lowest dose of radiation has the capability to cause complex DNA damage that can lead to a variety of permanent cellular changes; (2) the unique clustered characteristics of radiation damage, even at very low doses, enable it to stand out above the much larger quantity of endogenous DNA damage; (3) although a chromosome aberration may represent the rate-limiting initiating event for carcinogenesis, as is often assumed, direct evidence is still lacking; and (4) the extensive influence that dicentric aberrations have had on guiding extrapolations for radiation protection may be substantially misleading. Finally, some comments are offered on aspects that lie outside the current paradigm.
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PMID:Fifth Warren K. Sinclair Keynote Address: Issues in quantifying the effects of low-level radiation. 1982 Apr 49

It is known that numerous factors can influence radiation carcinogenesis in animals; these factors include the specific characteristics of the radiation (radiation type and dose, dose-rate, dose-fractionation, dose distribution, etc.) as well as many other contributing elements that are not specific to the radiation exposure, such as animal genetic characteristics and age, the environment of the animal, dietary factors and whether specific modifying agents for radiation carcinogenesis have been utilized in the studies. This overview focuses on the modifying factors for radiation carcinogenesis, in both in vivo and in vitro systems, and includes a discussion of agents that enhance (e.g., promoting agents) or suppress (e.g., cancer preventive agents) radiation-induced carcinogenesis. The agents that enhance or suppress radiation carcinogenesis in experimental model systems have been shown to lead to effects equally as large as other known modifying factors for radiation-induced carcinogenesis (e.g., dose-rate, dose-fractionation, linear energy transfer). It is known that dietary factors play an important role in determining the yields of radiation-induced cancers in animal model systems, and it is likely that they also influence radiation-induced cancer risks in human populations.
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PMID:Factors that modify radiation-induced carcinogenesis. 1982 Apr 53

It is clear from experimental studies that genotype is an important determinant of cancer susceptibility in general, and for radiation carcinogenesis specifically. It has become increasingly clear that genotype influences not only the ability to cope with DNA damage but also influences the cooperation of other tissues, like the vasculature and immune system, necessary for the establishment of cancer. Our experimental data and that of others suggest that the carcinogenic action of ionizing radiation (IR) can also be considered a two-compartment problem: while IR can alter genomic sequence as a result of DNA damage, it can also induce signals that alter multicellular interactions and phenotypes that underpin carcinogenesis. Rather than being accessory or secondary to genetic damage, we propose that such non-targeted radiation effects create the critical context that promotes cancer development. This review focuses on experimental studies that clearly define molecular mechanisms by which cell interactions contribute to cancer in different organs, and addresses how non-targeted radiation effects may similarly act though the microenvironment. The definition of non-targeted radiation effects and their dose dependence could modify the current paradigms for radiation risk assessment since radiation non-targeted effects, unlike DNA damage, are amenable to intervention. The implications of this perspective in terms of reducing cancer risk after exposure are discussed.
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PMID:Radiation carcinogenesis in context: how do irradiated tissues become tumors? 1982 Apr 54

Stem cells have been described in most adult tissues, where they play a key role in maintaining tissue homeostasis. As they self-renew throughout life, accumulating genetic anomalies can compromise their genomic integrity and potentially give rise to cancer. Stem cells (SCs) may thus be a major target of radiation carcinogenesis. In addition, unrepaired genotoxic damage may cause cell death and stem cell pool depletion, impairing lineage functionality and accelerating aging. Developments in SC biology enabled the characterization of the responses of stem cells to genotoxic stress and their role in tissue damage. We here examine how these cells react to ionizing radiation (IR), and more specifically their radiosensitivity, stress signaling and DNA repair. We first review embryonic SCs, as a paradigm of primitive pluripotent cells, then three adult tissues, bone marrow, skin and intestine, capable of long-term regeneration and at high risk for acute radiation syndromes and long-term carcinogenesis. We discuss IR disruption of the fine balance between maintenance of tissue homeostasis and genomic stability. We show that stem cell radiosensitivity does not follow a unique model, but differs notably according to the turnover rates of the tissues.
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PMID:Response of normal stem cells to ionizing radiation: a balance between homeostasis and genomic stability. 2011 35


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