Origins of Spontaneous Mutagenesis

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DESCRIPTION (provided by applicant): Approximately half of human cancer has no documented origin. It is often postulated that endogenous agents, including reactive oxygen species, are responsible for a significant fraction of these cancers. A presumed mechanism by which such agents act is via mutations, which in turn, may arise from DNA damage. Modified or damaged DNA has been detected at significant levels in a number of organs from nonsmokers with no known environmental exposures, lending support to this hypothesis. Mutations in proto-oncogenes and tumor suppressor genes have been found in a majority of human tumors, indicating that mutagenesis plays an important role in carcinogenesis. The lacI and lacZ rodents represent the only whole animal multi-organ systems applicable to the investigation of mutagenesis in vivo. Using such a system it has become possible to determine rates of spontaneous mutagenesis in any organ in vivo. As mutations in this system are neutral, the tissues accumulate new mutations over time, but previous mutations remain. Thus, only in organs where there is a substantial increase in spontaneous mutagenesis over time, is it practical to attempt to modify spontaneous mutagenesis. Based on reports from the lab of the PI and others, several such organs have been identified. In this application the effects of potential inhibitors on levels of spontaneous mutagenesis in two such organs (colon and bladder) will be monitored over time. The inhibitors have been chosen from classes of agents believed to prevent or reduce DNA damage from endogenous sources. These sources include oxidative agents, electrophiles, and flee radicals. The inhibitors include the antioxidant vitamins, E and C; the free radical scavenger amifostine (a known radioprotector); N-acetylcysteine, a potential radical scavenger which also enhances levels of glutathione; and 1,2-dithiole-3-thionine, a phase II enzyme inducer. In addition, the spontaneous mutation profile in older and younger animals will be compared with that of the oxidative mutagen, bleomycin, to determine whether oxidative damage is a major contributor to spontaneous mutagenesis. As mechanisms have been proposed by which the above inhibitors act, the results of this study will provide the basis for future studies on the detailed mechanisms of inhibition, and the origins of spontaneous mutagenesis. In view of the large numbers of human cancers likely attributable to endogenous sources, an understanding of spontaneous mutagenesis and the identification of inhibitory agents could have important public health consequences.