OXIDATIVE EVENTS IN CANCER THERAPY

本计划项目赠款的目标是促进对 氧化事件在癌症治疗中的作用。的影响 已建立的肿瘤生物学上的过氧化事件和 治疗引起的扰动将是所有项目的重点。 最新的脂类分析技术、电子顺磁技术 将使用共振(EPR)和抗氧化酶转基因。新的 脂类自由基和碳氢化合物的检测技术 组织培养细胞的产生将与已建立的 过氧化程度的量度。一种脂肪酸修饰模型的建立 为组织培养和饮食提供了强有力的工具 学习。四个项目，每个项目都由老牌的调查人员在 三个部门，提供综合的方法来实现目标。 项目1将研究氧化，特别是自由基的作用 在膜导向药物与DNA导向药物的化疗中。首字母 组织培养方面的研究将进行到实验阶段 小动物的治疗学。在项目2中， 将探索抗氧化酶的治疗方法。调制 使用转基因细胞系的酶，氧自由基的作用，影响 将包括脂质修饰和与过氧化的关联。 项目3将研究提高光动力学效率的方法 使用膜相关光敏剂治疗癌症 产生单线态氧。促氧化剂、抗氧化剂和 将考察双债券。项目4基于这样的假设： 由于脂质过氧化而形成的氧化脂肪酸产物 有助于某些抗癌疗法的细胞毒性作用。这个 总体目标是确定更稳定的脂质过氧化 暴露在氧化应激下的完整肿瘤细胞中形成的产物 并研究肿瘤细胞对它们的反应。互动 四个项目中的一个是涉及面广的。化疗和光动力疗法 将被包括在内。EPR Core A将提供最先进的专业知识 用于测量自由基的生成，并将尝试开发 EPR在生物系统中应用的新技术。核心B 将为所有项目提供脂质分析技术。核心C将 测定抗氧化物酶蛋白、mRNA和基因拷贝以及 将抗氧化物酶正反义cDNA导入不同细胞 台词。总而言之，该计划将利用自然的 调查人员在四个相关项目中的互动，每个项目 利用四个科学核心，解决一个重要的 癌症实验疗法研究不足的方面。

The goals of this Program Project Grant is to advance understanding of the role played by oxidative events in cancer therapy. The influence of peroxidative events on the biology of established tumors and the perturbations induced by treatment will be the focus of all projects. State-of-the-art techniques in lipid analysis, electron paramagnetic resonance (EPR) and antioxidant enzyme transfections will be used. New techniques for detecting lipid-derived free radicals and hydrocarbon generation from tissue culture cells will be paralleled by established measures of peroxidation. A model of fatty acid modification developed by participants provides a powerful tool for tissue culture and dietary studies. Four projects, each directed by established investigators in three departments, provide and integrated approach to the objectives. Project 1 will examine the role of oxidation and especially free radicals in chemotherapy with membrane-directed vs DNA-directed drugs. Initial studies in tissue culture will be carried through to experimental therapeutics in small animals. In Project 2 the importance of antioxidant enzymes to therapy will be explored. Modulation of the enzymes using transfected cell lines, role of oxygen radicals, effect of lipid modification and correlation with peroxidation will be encompassed. Project 3 will investigate ways to enhance efficacy of photodynamic therapy of cancer using membrane-associated photosensitizers that generate singlet oxygen. The role of pro-oxidants, antioxidants and double bonds will be examined. Project 4 is based on the hypothesis that the oxidized fatty acid products formed as a result of lipid peroxidation contribute to the cytotoxic effect of certain anticancer therapies. The overall objectives are to identify more-stable lipid peroxidation products formed in intact neoplastic cells exposed to oxidative stress and investigate how neoplastic cells respond to them. The interaction of the four projects is extensive. Chemotherapy and photodynamic therapy will be included. The EPR Core A will provide state-of-the-art expertise for measurement of free radical generation and will attempt to develop new techniques for the application of EPR to biologic systems. Core B will provide lipid analysis techniques for all projects. Core C will determine antioxidant enzyme protein, mRNA and gene copy as well as transfect antioxidant enzyme sense and antisence cDNAs into various cell lines. In summary, this Program will take advantage of the natural interactions of the investigators in four related projects, each utilizing four scientific cores, to solve an important and underinvestigated aspect of cancer experimental therapies.