Historically, natural products have proven a rich source of anticancer drugs. A recent review estimated that 74% of the clinically used drugs in this field of medicine are natural products or are derived from natural product lead compounds. This statistic suggests that it is important for the cancer community to continue studies of novel anticancer agents isolated from natural sources. The work described in this proposal is designed to characterize the chemical and biological mechanisms of the antineoplastic, DNA- damaging natural product leinamycin. Leinamycin displays very potent activity against human cancer cell lines (e.g. IC50 of 0.014 ng/mL - this translates to an IC50 of 27 nM - against HeLa cells) and is currently in development as a potential anticancer agent at Kyowa Hakko Kogyo Pharmaceuticals. Exposure of duplex DNA to leinamycin leads to production of a rapid """"""""burst"""""""" of apurinic sites (AP sites). In addition, reaction with leinamycin converts the attacking thiol residue into a persulfide (RSSH) species that has the potential to cause oxidative stress in cells. Leinamycin does not generate DNA-crosslinks or double-strand breaks, but displays biological activity comparable to clinically used agents that do. Thus, the unusual DNA-damaging properties of leinamycin may represent a new biochemical route to potent anticancer activity. Experiments described in this proposal are designed to relate leinamycin's unique biochemical properties to its potent activity against cancer cell lines. We will test the hypothesis that leinamycin's ability to simultaneously generate a burst of AP sites along with oxidative stress account for its very potent biological activity. The work is divided into the following five Specific Aims: 1. Test the Hypothesis That the Rapid Generation of AP Sites Is Central to Leinamycin's Cancer Cell Killing Properties. 2. Explore the Chemical Basis for the Exceedingly Rapid Depurination of the Leinamycin-Guanine Adduct in Duplex DNA. 3. Test the Hypothesis That Leinamycin Causes Oxidative Stress In Human Cancer Cell Lines. 4. Explore the Chemical Mechanisms by Which Leinamycin Generates Reactive Oxygen Species Under Physiologically Relevant Conditions. 5. Characterize Cellular Responses to Leinamycin.
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