In conjunction with advances that have been made in describing the molecular nature of mammalian cell biology, a clearer understanding of the role of chemicals in cancer cause, prevention and treatment has emerged. As related to these broad subject areas, the present proposal deals primarily with characterizing the interaction of such chemicals with DNA. Factors leading to or diminishing this interaction, and the consequences or advantages thereof, will also be investigated. Firstly, it is well-known that chemicals play an important role in the etiology of several types of human cancer. Conversely, a variety of naturally occurring and synthetic substances have been discovered that inhibit chemically-induced neoplasia. In particular, epidemiological evidence suggests a reduced incidence of lung cancer among individuals that consume adequate quantities of retinoids. Studies are proposed to examine the mechanism of chemoprotective activity employing cultured human bronchus as a model system. Cultures maintained in the presence or absence of retinoids will be treated with benzo(a)pyrene or the proximate carcinogen, (-)-trans-7,8-dihydroxy-7,8-dihydrobenzoa(a)pyrene. The effect of retinoids on carcinogen binding and metabolism, and related factors such as bronchial morphology and enzymic composition will be determined. Secondly, it has recently been found that steviol, the aglycone of the commercial sweetening agent stevioside, is mutagenic. This is important since the parent compound is consumed by humans, and little is known concerning ent-kaurene-mediated mutagenicity. Studies will be performed to thoroughly characterize pathways of metabolic activation and detoxification, and the nature of the interaction of steviol metabolites with DNA. Lastly, it is established that many cancer chemotherapeutic agents function by mechanisms involving interaction with DNA or tubulin. Attempts will be made to establish novel methodology for the isolation of new antitumor agents from crude extracts by virtue of interaction with DNA or tubulin. Depending on the structural characteristics and biological activity of the resulting substances, mechanistic studies may be performed. Thus, over the course of the award period, investigations will be performed to examine (1) the mechanism of chemoprotective activity of retinoids that may modulate carcinogen-macromolecule interactions (2) factors involved in ent-kaurene interactions with DNA that are mutagenically relevant, and (3) the potential value of DNA and tubulin as biospecific probes for the isolation of novel, biologically-active substances. The respective long-term objectives are to provide a better understanding of cancer prevention and cause, and a rational approach of obtaining new agents that may be of value in the treatment of cancer.
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