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Append ix G THE ASSOCIATION OF DNA DAMAGE WITH CANCER-INITIATING EVENTS Some of the reasons for associating cancer initiation with damage to DNA are as follows: 1. Many carcinogenic agents are electrophilic in nature (attracted to negatively charged particles) and react with cellular macromolecules. There is an association between the mutagenicity of compounds (their reactivity with DNA) and their carcinogenicity, although one must remember the necessity for activating inactive mutagenic compounds. In animal carcinogenic test systems, the animals contain the necessary activating enzymes. Within families of active metabolites, such as the diolepoxides of benzo(a)pyrene, there is a very close association between mutagenicity and carcinogenicity, and a similar association is found for nitrosamines in liver-cell-activated mutagenicity and liver carcinogenicity. 2. The disease xeroderma pigmentosum is associated with a very high skin cancer prevalence, and the cancers are on the sun-exposed areas of the body. The cells of individuals with this disease are defective in one or more mechanisms that repair ultraviolet damage to DNA. Defects in repair are associated with a 103- to 104-fold higher skin cancer prevalence in xeroderma pigmentosum individuals than in the average population. 3. If the thymidine in the DNA of cells in culture is substituted by the analog bromodeoxyuridine, the cells become very sensitive to W -B because bromodeoxyuridine has a much higher absorption coefficient in the W-B than does thymidine. Substitution with bromodeoxyuridine is a way to sensitize cells to W-B and the sensitization may be detected either in terms of cell killing, neoplastic 331

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332 transformation, or the ability of W-B to make single strand breaks in the DNA. In this system, there is a close association between DNA damage and neoplastic transformation. (Under normal conditions, cells in culture do not grow indefinitely, but are inhibited when they grow to sufficient numbers that they begin to contact one another. This contact inhibition may be destroyed by radiation so that the cells continue to proliferate and make so-called "transformed" foci. In many instances, such foci give rise to tumors when the cells from a focus are transplanted into appropriate mouse strains.) 4. Certain species of fish grow in clones. Cells from one member of the clone may be removed, irradiated in vitro, and injected back into other members of the clone. When this is done for thyroid cells of the species Poecilia Formosa, thyroid tumors develop in the recipients. If, however, visible light exposure follows the ultraviolet exposure, that is to say, the cells are subjected to photoreactivation, no tumors develop. Since photoreactivation is diagnostic for pyrimidine dimers (Chapter 3) in DNA, these experiments not only imply damage to DNA in tumor production but also implicate a specific photoproduct--pyrimidine dimers. 5. The action spectrum for neoplastic transformation is similar to that for affecting DNA in mammalian cells (Chapter 3).