BIOLOGICAL CONSEQUENCES OF PROTEIN OXIDATION

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Reactive oxygen compounds such as O2- and H2O2 are generated under numerous circumstances in vivo and in vitro. In the presence of transition metals (e.g., iron, copper), these compounds induce covalent modifications in cellular and purified macromolecules including proteins, DNA, and lipids. Oxidants are thought to contribute to the etiology of a wide array of pathologic conditions including ischemia-reperfusion injury, atherosclerosis, chronic inflammation, and cancer. The focus of our work is to elucidate the consequences of exposure of biological substrates to oxidative stress. In these studies, we examined mechanisms of induction of cytotoxicity by H2O2 with emphasis on understanding the ramifications for tumor cell biology. Most pre-clinical safety studies use animals for the establishment of expected toxicities. These tests are costly monetarily and in terms of animal life. We are setting up a battery of in vitro pre-clinical assays to assess cell killing. The field of cytotoxicity has advanced so rapidly that methods that were accepted 10 years ago are no longer adequate. For example, we now know that cells dying by apoptosis exclude vital dyes and that agents that kill by this mechanism can be mistakenly diagnosed as non-toxic. The development of valid in vitro models for cytoxicity will enable us to promote better pre-clinical testing and will enhance our ability to regulate anti-cancer drugs. Our work shows that the mechanism through which a drug kills tumor cells will impact its efficacy and side effects. Cytotoxicity is also relevant for regulating thrombolytic agents since thrombolysis can lead to reperfusion injury, thought to be caused by oxygen radicals. Future treatments for infarction may involve combination therapies that include anti-oxidants. Our work gives the agency the expertise required to regulate novel therapeutic approaches.