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RADIATION CARCINOGENESIS

Radiant energy, whether in the form of the UV rays of sunlight or as ionizing electromagnetic and particulate radiation, can transform virtually all cell types in vitro and induce neoplasms in vivo in both humans and experimental animals. UV light is clearly implicated in the causation of skin cancers, and ionizing radiation exposure from medical or occupational exposure, nuclear plant accidents, and atomic bomb detonations have produced a variety of forms of malignant neoplasia. Although the contribution of radiation to the total human burden of cancer is probably small, the well-known latency of radiant energy and its cumulative effect require extremely long periods of observation and make it difficult to ascertain its full significance. An increased incidence of breast cancer has become apparent decades later among women exposed during childhood to the atomic bomb. The incidence peaked during 1988–1992 and then declined during the period 1993–1997.[158] Moreover, radiation's possible additive or synergistic effects with other potential carcinogenic influences add another dimension to the picture. The effects of UV light on DNA differ from those of ionizing radiation. The cellular and molecular effects of ionizing radiation are discussed in Chapter 9.

Ultraviolet Rays

There is ample evidence from epidemiologic studies that UV rays derived from the sun induce an increased incidence of squamous cell carcinoma, basal cell carcinoma, and possibly malignant melanoma of the skin.[159] The degree of risk depends on the type of UV rays, the intensity of exposure, and the quantity of light-absorbing "protective mantle" of melanin in the skin. Persons of European origin who have fair skin that repeatedly gets sunburned but stalwartly refuses to tan and who live in locales receiving a great deal of sunlight (e.g., Queensland, Australia, close to the equator) have among the highest incidence of skin cancers in the world. The UV portion of the solar spectrum can be divided into three wavelength ranges: UVA (320 to 400 nm), UVB (280 to 320 nm), and UVC (200 to 280 nm). Of these, UVB is believed to be responsible for the induction of cutaneous cancers. UVC, although a potent mutagen, is not considered significant because it is filtered out by the ozone shield around the earth (hence the concern about ozone depletion). UV rays have a number of effects on cells, including inhibition of cell division, inactivation of enzymes, induction of mutations and, in sufficient dosage, death of cells. The carcinogenicity of UVB light is attributed to its formation of pyrimidine dimers in DNA. This type of DNA damage is repaired by the nucleotide excision repair (NER) pathway. There are five steps in NER: (1) recognition of the DNA lesion, (2) incision of the damaged strand on both sites of the lesion, (3) removal of the damaged nucleotide, (4) synthesis of a nucleotide patch, and (5) its ligation. In mammalian cells, the process may involve 30 or more proteins. It is postulated that with excessive sun exposure, the capacity of the NER pathway is overwhelmed; hence, some DNA damage remains unrepaired. This leads to large transcriptional errors and, in some instances, cancer. The importance of the NER pathway of DNA repair is most graphically illustrated by a study of patients with the hereditary disorder xeroderma pigmentosum. This autosomal recessive disorder is characterized by extreme photosensitivity, a 2000-fold increased risk of skin cancer in sun-exposed skin and, in some cases, neurologic abnormalities. The molecular basis of the degenerative changes in sun-exposed skin and occurrence of cutaneous tumors rests on an inherited inability to repair UV-induced DNA damage. Xeroderma pigmentosum is a genetically heterogeneous condition, with at least seven different variants. Each of these is caused by a mutation in one of several genes involved in NER.[160] As with other carcinogens, UVB also causes mutations in oncogenes and tumor suppressor genes. In particular, mutant forms of the RAS and p53 genes have been detected both in human skin cancers and in UVB-induced cancers in mice. These mutations occur mainly at dipyrimidine sequences within the DNA, thus implicating UVB-induced genetic damage in the causation of skin cancers. In animal models, p53 mutations occur early after exposure to UVB, before the appearance of tumors.



Ionizing Radiation

Electromagnetic (x-rays, rays) and particulate (particles, particles, protons, neutrons) radiations are all carcinogenic. The evidence is so voluminous that a few examples suffice.

Many of the pioneers in the development of X-rays developed skin cancers. Miners of radioactive elements in central Europe and the Rocky Mountain region of the United States have a tenfold increased incidence of lung cancers. Most telling is the follow-up of survivors of the atomic bombs dropped on Hiroshima and Nagasaki. Initially, there was a marked increase in the incidence of leukemias—principally acute and chronic myelocytic leukemia—after an average latent period of about 7 years. Subsequently the incidence of many solid tumors with longer latent periods (e.g., breast, colon, thyroid, and lung) increased. Residents of the Marshall Islands were exposed on one occasion to accidental fallout from a hydrogen bomb test that contained thyroid-seeking radioactive iodines. As many as 90% of the children under age 10 years on Rongelap Island developed thyroid nodules within 15 years, and about 5% of these nodules proved to be thyroid carcinomas. A marked increase in the incidence of thyroid cancer has also been noted in areas exposed to the fallout from the nuclear power plant accident in Chernobyl in 1986. In addition to approximately 30 deaths that occurred at the time of the accident, more than 2000 cases of thyroid cancers have been recorded in children living in the area.[161] Cytogenetic studies have detected an elevated frequency of chromosomal alterations in persons who did cleanup work at the power plant after the accident.[162] It is evident that radiant energy—whether absorbed in the pleasant form of sunlight, through the best intentions of a physician, or by tragic exposure to an atomic bomb blast or radiation released by nuclear plant accidents—has awesome carcinogenic potential. Even therapeutic irradiation has been documented to be carcinogenic. Thyroid cancers have developed in approximately 9% of those exposed during infancy and childhood to head and neck radiation. The previous practice of treating ankylosing spondylitis with therapeutic irradiation yielded a 10- to 12-fold increase in the incidence of leukemia years later.

In humans, there is a hierarchy of vulnerability of different tissues to radiation-induced cancers. Most frequent are the leukemias, except for chronic lymphocytic leukemia, which, for unknown reasons, almost never develops after radiation. Cancer of the thyroid follows closely but only in the young. In the intermediate category are cancers of the breast, lungs, and salivary glands. In contrast, skin, bone, and the gastrointestinal tract are relatively resistant to radiation-induced neoplasia, even though the gastrointestinal epithelial cells are vulnerable to the acute cell-killing effects of radiation, and the skin is in the pathway of all external radiation. Nonetheless, the physician dare not forget: practically any cell can be transformed into a cancer cell by sufficient exposure to radiant energy.


Date: 2016-04-22; view: 703


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