Health Effects of Exposure to Low Levels of Ionizing Radiation BEIR V (1990) / Chapter Skim
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3 Mechanisms of Radiation-Induced Cancer
3 Mechanisms of Radiation-Induced Cancer
Pages 135-160
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From page 135... ...
three distinct and separate stages have been identified in experimental carcinogenesis: initiation, promotion, and progression. The fact that the cumulative incidence of cancer increases approximately as the seventh power of age during adult life prompted early investigators to postulate the existence of seven successive events, or steps, in the conversion of a normal cell into a cancer cell; these events were thought to involve mutational changes in the broadest sense (Arson.
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From page 136... ...
Nevertheless, altered gene expression does not exclude the possibility that premalignant cells might undergo mutation during their conversion to cancer cells. Initiation, Promotion, and Progression in Carcinogenesis The following generalizations about the process of carcinogenesis are noteworthy: (1)
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From page 137... ...
This concept of carcinogenesis as a two-stage process was suggested originally by studies of tumor induction in mouse skin in which a dose of chemical carcinogen that was too small to cause a detectable increase in the incidence of tumors was found to induce a high incidence of tumors if it was followed by repeated administration of a suitable promoting agent, an agent that did not cause tumors when administered alone (Bo74a, Beam. A synergistic interaction between the initiating effects of radiation (or various chemicals)
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Tissue irritation, which stimulates cell division, was recognized long ago to increase the probability of tumor development; for example, following carcinogen treatment of the skin or liver, wounding of the skin or partial hepatectomy enhances tumor formation in the skin or liver, respectively (Sump. Similarly, the carcinogenic effects of memo alpha radiation on the lung of the hamster are enhanced by repeated instillation of saline into the airway, which stimulates proliferation of pulmonary epithelial cells (Li78, Sham.
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These free radicals can, in turn, damage DNN It is noteworthy, therefore, that free radical-generating agents can act as tumor promoters (Ke86) and that inhibitors of free radical reactions can suppress tumor promotion in some systems (S183~.
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Cell survival and transformation frequency cannot be assessed from the same culture dishes. Results can be expressed as transformation frequency per surviving cell, but because the transformation frequency observed is a function of the number of viable cells seeded per culture dish, the data can also be expressed in terms of the number of foci per dish or the fraction of culture dishes bearing foci.
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For gamma rays and other low-LET radiations, the cell survival curve is characterized by a broad initial shoulder
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The curve represents a balance between transformation and cell killing and indicates that cells destined to become transformed have a survival response similar to that of untransformed normal cells. The peak of the dose-response curve for transformation frequency per initial cell at risk often reaches higher values for densely ionizing radiations, such as neutrons and alpha particles than for x rays or gamma rays.
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The cell survival curve for gamma rays has a broad initial shoulder, while that for helium-3 ions is an exponential function of dose. For high-LET particles, the transformation frequency peaks at a much lower dose than for gamma rays and reaches a value that is higher by a factor of about 5 than is the case for gamma rays (Ha87a)
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From page 144... ...
It was also demonstrated that potentially lethal damage was repaired in x-irradiated 3T3 cells and was not repaired in alpha-particle irradiated cells, resulting in a high RBE value for oncogenic transformation in alphairradiated plateau-phase cultures. Similar findings have also been reported by Hall and Hei who used
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An example of the suppressive effect of the protease inhibitor antipain on radiation transformation and the TPA enhancement of radiation transformation is shown in Figure 3-6. Other examples of agents which suppress radiation transformation are selenium (Figure 37)
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FIGURE 34 Dose-response curve for the induction of radiation transformation, with or without enhancement by TPA. Note how a promoter changes a linear quadratic response to a linear one (Kemp.
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on radiation transformation in vitro, both with and without promotion By TPA (Kemp. genes that are thought to be the sites of oncogenic somatic mutations.
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at 3 Gy on radiation transformation (Ha87a)
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A role for oncogenes in the earliest stage of oncogenic transformation could be better supported if individuals who carried such mutations in their germ lines were found. This has not been found as yet in humans, but susceptible mice have been produced experimentally by transgenically introducing an activated oncogene into the germ line.
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They also have a lesser predisposition to osteosarcoma in the absence of irradiation. In either case, the genetic change in the tumor cells is the loss of the two normal alleles of the retinoblastoma gene; thus, this gene is a tumor-suppressor gene for osteosarcoma (Ha85)
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From page 151... ...
Thus, in xeroderma pigmentosum a defect in excision repair permits an increased rate of mutations at all genetic loci in cells exposed to sunlight. Ataxia telangiectasia predisposes the chromosome to breakage, especially in lymphocytes; the underlying molecular defect is not known, but it is thought to involve a defect in DNA repair.
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From page 152... ...
The situation is less clear for the risk factors for lung cancer. The BEIR IV Committee found that smoking and prolonged exposure to inhaled alpha-particle emitters interacted in a multiplicative fashion, or nearly so, with the result that the increased risk of radiogenic lung cancer in those of a given smoking status was proportional to the baseline risk for the same smoking status (NRC88~; however, this may not be the case for acute exposures to x rays and gamma rays.
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1987. The action of chemical carcinogens and oncogenic retroviruses in mouse skin tumor induction.
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Free radicals in promotion a chemical pathology study section workshop. Cancer Res.
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1986. Oneogenes activated in radiation-induced rat skin tumors.
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1987. Ionizing radiation enhances malignant progression of mouse skin tumors.
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1986. Role of free radicals in the initiation and promotion of radiation-induced and chemical carcinogen induced cell transformation.
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1979. Effect of tumor promoters, protease inhibitors, and repair processes on X ray-induced sister ehromatid exchanges in mouse cells.
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1983. Studies on the mechanism of action of antitumor promoting agents: suggestive evidence for the involvement of free radicals in promotion.
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1984. The selective advantage of cancer cells; a consequence of genome mobilization in the course of the induction of DNA repair processes?
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