BIOLOGICAL CONSEQUENCES OF PROTEIN OXIDATION

活性氧化合物，如O2-和H2O2，在 体内和体外的许多情况下。在……面前 过渡金属(如铁、铜)，这些化合物诱导共价 对细胞和包括蛋白质在内的纯化大分子的修饰， DNA和脂类。氧化剂被认为是导致一种 包括缺血-再灌注损伤在内的一系列病理情况， 动脉粥样硬化、慢性炎症和癌症。我们的工作重点是 是为了阐明生物底物暴露在 氧化应激。在这些研究中，我们检查了诱导的机制 对过氧化氢的细胞毒性的研究，重点了解其影响 为了肿瘤细胞生物学。 大多数临床前安全性研究使用动物来建立 预期的毒性。这些测试在经济上和在以下方面都是昂贵的 动物的生活。我们正在建立一组体外临床前检测 来评估细胞杀伤力。细胞毒性领域进展如此之快 10年前被接受的方法已经不再适用。为 例如，我们现在知道，通过凋亡而死亡的细胞不包括重要的染料和 通过这种机制杀人的特工可能会被误诊为 无毒。有效的细胞毒性体外模型的开发将 使我们能够促进更好的临床前测试，并将增强我们的 监管抗癌药物的能力。我们的工作表明，这种机制 药物通过哪些途径杀死肿瘤细胞会影响其疗效和副作用 效果。细胞毒性也与调节溶栓剂有关 自溶栓后可导致再灌注损伤的药物，被认为 是由氧自由基引起的。未来对脑梗塞的治疗可能包括 包括抗氧化剂在内的综合疗法。我们的工作给了我们 该机构拥有规范新治疗方法所需的专业知识。

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.