The carcinogenic potential of ionizing radiation was soon recognized after Roentgen's discovery of x-rays in December 1895. The first report of leukemia in five radiation workers dates back to 1911.43 (Marie Curie and her daughter, Irene, are both thought to have died from complications of radiation-induced leukemia.) Follow-up studies on atomic bomb survivors in Hiroshima and Nagasaki have confirmed that ionizing radiation is a "universal carcinogen" in that it induces tumors in most tissues of most species at all ages, including the fetus. The universal nature of radiation as a carcinogen is based on its ability to penetrate cells and deposit energy within them in a random manner, unaffected by the usual cellular barriers presented to chemical agents. As a consequence, all cells of the body are susceptible to ionizing radiation, and the amount of damage will depend on the physical parameters that determine the radiation dose received by a particular cell or tissue. Radiation can induce DNA lesions including damage to nucleotide bases, cross-linking, and DNA single- and double-strand breaks (DSBs). It is now accepted that misrepaired DSBs are the main lesions of importance in the induction of both chromosomal abnormalities and gene mutations.44,45
DSBs in DNA are produced when the two complementary DNA strands are simultaneously broken at sites close enough to one another and cannot be kept juxtaposed. The two fragments generated by this process are liable to become physically dissociated, making repair difficult and providing an opportunity for inappropriate recombination with other sites of the genome. However, despite posing major threats to genomic integrity, DSBs can be deliberately produced for "physiologic" purposes in the cells of the immune response. Moreover, DSBs are potent inducers of mutations and cell death.
There are two main pathways for DNA DSBs repair: homologous recombination (HR) and nonhomologous end joining (NHEJ). HR requires that the damaged chromosome enter into synapsis with, and retrieve genetic information from, an undamaged DNA molecule with which it shares extensive sequence homology; NHEJ does not have these requirements. As a consequence, NHEJ is more prone to error than HR and may facilitate the production of chromosomal rearrangements and other large-scale changes frequently occurring in irradiated cells.46,47 As a consequence of DSBs, large-scale mutational events, such as deletions, chromosomal rearrangements, and recombinational processes, are associated with ionizing radiation. However, the search for genetic changes specifically associated with radiation has been disappointing, and there is no evidence of site specificity for mutations induced by radiation. Studies of oncogene activation or tumor suppressor gene inactivation in radiation transformation in vitro have been also disappointing. As we have seen in Chapter 1, however, there is increasing evidence that genomic instability may represent the earliest and most important event in both radiation and chemical carcinogenesis and may represent, as well, the best explanation for the reported lack of specificity of ge-nomic lesions induced by both radiation and chemical carcinogens.
As outlined, genomic instability is a hallmark feature of nearly all solid tumors and adult-onset leukemia. Genomic instability is the process by which the entire cellular genome becomes more prone than a normal
(stable) genome to make mistakes in the arrangement of chromsomes and fragments of chromosomes within the cell itself and, during mitosis, within the daughter cells. As already mentioned, the root source of genomic instability has to be researched in the processes of DNA damage and repair. As a matter of fact, intrachromoso-mal genomic instability in cancer reflects an increased rate of appearance of DNA alterations in tumor cells, which arises from either an increased rate of damage overwhelming the ability of a normal repair system to restore genetic integrity or a defective repair system unable to cope with a normal rate of damage. It is clear that preserving genomic integrity is of immense relevance for cells and organisms. That is evident when we consider that our genome contains around 250 genes for the purpose of DNA repair, 230 for high-fidelity DNA replication, and 500 for chromosome segregation, cell cycle checkpoints, telomeres, centromeres, and so on.
When the cell becomes unable to repair DNA damage for either of the reported conditions, genomic instability will follow and will propagate to daughter cells for a number of generations, thus amplifying both the number of damaged cells and the amount of damage per cell until, eventually, transformation occurs and cancer develops.48
Evidence has been presented that an unstable genome persists for at least 12 and perhaps 25 population doublings after radiation exposure. This transmissible instability may enhance the rate at which spontaneous mutations arise in the descendants of the irradiated cells. The widespread and apparently random nature of ge-nomic instability may account for the reported lack of specificity of genomic lesions induced by both radiation and chemicals; also, genomic instability tells us that ionizing radiation may produce nontargeted effects, or, in other words, important genetic consequences of radiation may arise in cells born from the irradiated ones that in themselves received no direct nuclear exposure.
At this point, it will be of interest to notice that early investigations have shown that cytoplasmic irradiation with low fluences of a particles can induce a significant frequency of mutations in mammalian cells,49 thus indicating that nuclear irradiation is not required for the production of important genetic effects. The production of gene mutations after cyto-plasmic irradiation has been hypothesized to involve an enhanced production of reactive oxygen species (ROS) within the process globally indicated as oxida-tive stress. As demonstrated, DNA can be damaged in a sequence-specific manner by oxidative stress.50 Ox-idative stress results when the balance between the production of ROS overrides the antioxidant capabilities of the target cells; the interaction between reactive oxygen and critical cellular macromolecules may then occur,51 with subsequent modification of cellular proteins, lipids, and DNA, which results in altered target cell function.
One further step in the mechanism of oxidative stress within radiation-induced carcinogenesis is represented by the so-called bystander effect, that is, the production of biologically relevant effects in cells that receive no direct radiation exposure. Evidence has been presented that cells irradiated with a particles secrete cytokines and other factors that lead to enhanced production of oxygen species in cells not directly irradiated, with subsequent damage of their proteins, lipids, and DNA52 and have increased potential for genomic instability and cancer transformation (Figure 2.4). The International Agency for Research in Cancer (IARC) has defined chemical carcinogenesis as "the induction by chemicals of cancers that are not usually observed, the earlier induction by chemicals of cancers that are usually observed, and the induction by chemicals of more cancers than are usually found."53 Although operationally useful, this definition does not address the fundamental distinction between direct-acting carcinogens and those acting indirectly through complex interactions with the test organism.54 In 1973 the term "genotoxicity" was introduced to denote toxic, lethal, and heritable effects to karyotic and extrakaryotic material in germinal and somatic cells55 and was assumed to be the basis of carcinogenicity of all chemicals. Subsequently, this paradigm was largely questioned, and the distinction between DNA-reactive (genotoxic) and epigenetic (nongenotoxic) carcinogens was well established.56 DNA-reactive carcinogens are those that act in the target cell of tissue(s) to form DNA adducts that are the basis for neoplastic transformation. Epigenetic carcinogens lack chemical reactivity and hence do not form DNA adducts, but produce their effects indi-
Ionizing radiation and chemicals
Ionizing radiation and chemicals
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FIGURE 2.4. Proposed mechanisms of radiation and chemical carcinogenesis.
rectly (Figure 2.4). A comprehensive list of chemical carcinogens classified according to this distinction is reported by Williams.56 The past two decades have witnessed an extraordinary impulse of the genetics, particularly under the influence of the Human Genome Project, and cancer has been increasingly viewed as a genetic disease. This radical and partial view of the pathogenesis of human cancer has been tempered by the discovery that gene expression can be modulated in the absence of structural damage of the genes themselves. Therefore, cancer should be more appropriately defined as a "disease of genes," implying that while an altered gene expression is almost invariably found in cancer, it does not necessarily derive from spontaneous gene changes but from either a direct or indirect insult on the DNA structure.
The paradigm of chemical carcinogenesis represents a milestone in the understanding of the real complexity inherent the processes of cell transformation and cancer development. As we have seen, together with "direct" DNA-reactive chemicals, a number of chemicals must be taken into account whose action, through the intermediary of oxidative stress, can modify intercellular communication, protein-kinase activity, membrane structure and function, and gene expression, to finally lead to deregulation of cell growth.57
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