Most agents that either cause or cure cancer react with DNA to form products collectively referred to as adducts. Adducts are believed to act as the functional precursors to cancer and possibly other genetic diseases by causing mutations or even more complex genetic events. Adducts also can kill cells by interfering with normal replication and transcription; the killing property of DNA damaging agents has been exploited in the design of antitumor drugs. The objective of the research of this laboratory is to investigate the mechanisms of mutagenesis, genotoxicity and DNA repair of a series of adducts formed by DNA damaging agents of relevance to human health. The carcinogenic chemicals we investigate include mycotoxins, aromatic amines, short-chain alkylating agents, organic carbonyl compounds and vinyl halides. We also study inorganic complexes of, and related to, the antitumor drug cisdiamminedichloroplatinum (II). Finally, we are investigating the genetic after-effects of DNA damage by ionizing radiation and oxidation. To accomplish our goals, we use the tools of chemical synthesis and recombinant DNA technology to construct viral or plasmid vectors that contain, at specific genome locations, the known DNA adducts formed by the DNA damaging agents listed above. Site-specifically modified genomes are then introduced into bacterial or mammalian cells, where the single DNA lesion is acted upon in a presumably normal way by the cell's replication/repair systems. We next characterize the amount and type of mutations induced through misreplication or misrepair of the adducted genome. We also determine the relative genotoxic potentials of the individual adducts formed by the chemicals (or radiations) under study. With this information, we attempt to establish formal rules that relate the structure of the DNA lesion with its biological effects. Finally, since DNA repair proteins modulate the genotoxicity of many antitumor drugs, as well as many chemical and physical carcinogens, we attempt to elucidate the biochemical pathway(s) by which the DNA adducts are repaired in mammalian cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Unknown (R35)
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Special Emphasis Panel (SRC (N2))
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Massachusetts Institute of Technology
Other Domestic Higher Education
United States
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