Conference Grant: "DNA Alkylation: From Natural Products to Chemotherapy"

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DESCRIPTION (provided by applicant): This proposal is a request for financial support of a half-day symposium entitled: "DNA Alkylation: From Natural Products to Chemotherapy" to take place at the 232nd National Meeting of the American Chemical Society on September 10-14, 2006 in San Francisco, California. The symposium will be sponsored by the Division of Chemical Toxicology and co-sponsored by the Division of Medicinal Chemistry. The event is designed as a forum for discussion of current thinking regarding the chemical and biological mechanisms by which DNA-alkylating agents derive their medicinally useful properties. DNA-alkylating agents were among the first chemotherapeutic agents successfully employed for the treatment of cancer in humans in the 1940s. Since that time, a large number of DNA-alkylating anticancer drugs have been developed and these compounds now play a central role in cancer chemotherapy due to their efficacy in treating various cancers. Even as fundamentally new approaches to cancer chemotherapy are developed, it is likely that DNA-alkylating drugs will remain widely used. This class of drugs will continue to see widespread use because of their well-established success in treating certain cancers and also because many of the new approaches for fighting cancer, including inhibition of angiogenesis, immunotherapies, and modulation of the cell cycle, are most effective when used in combination with cytotoxic agents such as the DNA alkylators. Thus, there is an ongoing need to understand the chemistry and biology of clinically-used DNA-alkylating drugs and for the development of chemically novel DNA-alkylating agents for potential use as new chemotherapeutic agents. The symposium will focus on three areas that hold promise for the development of effective DNA-alkylating anticancer drugs. (1) Characterization of novel DNA alkylating natural products. Historically, natural products have proven a rich source of anticancer drugs. In this symposium, the chemistry and biology of several structurally novel natural products with very potent activity will be discussed including duocarmycin, azinomycin, mitomycin C, the illudins, and leinamycin. (2) Examination of how the chemical structure of a DNA alkylation adduct relates to the biological response that it elicits. This topic will be considered for all agents, but especially for mitomycin C, where a variety of structurally diverse adducts have been shown to induce very different biological responses. A clear understanding of how adduct structure relates to cytotoxicity would be very useful in anticancer drug development. (3) Finally, the influences of enzyme-mediated processes, such as DNA repair, on cell killing by alkylating agents will be examined. In this vein, the rational design of DNA-alkylating agents that selectively kill cancer cells will be discussed.