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  • Title: [Prevention of cancer and the dose-effect relationship: the carcinogenic effects of ionizing radiations].
    Author: Tubiana M.
    Journal: Cancer Radiother; 2009 Jul; 13(4):238-58. PubMed ID: 19539515.
    Abstract:
    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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