OXIDATIVE EVENTS IN CANCER THERAPY

该计划项目补助金的目标是促进对 氧化事件在癌症治疗中的作用。 的影响 过氧化事件对已建立的肿瘤生物学的影响， 所有项目都将重点关注因处理而引起的扰动。 脂质分析、电子顺磁分析的最新技术 将使用共振（EPR）和抗氧化酶转染。 新 用于检测脂质衍生的自由基和烃的技术 将通过建立组织培养细胞的代 过氧化的措施。 脂肪酸改性模型的建立 提供了一个强大的工具，组织培养和饮食 问题研究 四个项目，每个项目都由 三个部门，提供和综合的方法来实现目标。 项目1将研究氧化的作用，特别是自由基 在膜导向和DNA导向的化疗中。 初始 组织培养研究 将进行实验性的 小动物的治疗。 在项目2中， 抗氧化酶的治疗将被探索。 调制 使用转染细胞系的酶，氧自由基的作用， 将包括脂质修饰和与过氧化的相关性。 项目3将研究如何提高光动力的功效 使用膜结合光敏剂的癌症治疗，所述光敏剂 产生单线态氧。 促氧化剂、抗氧化剂和 将检查双键。 项目4基于以下假设： 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。 的 总体目标是确定更稳定的脂质过氧化作用 暴露于氧化应激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。 的相互作用 这四个项目是广泛的。 化疗和光动力疗法 将包括在内。 EPR核心A将提供最先进的专业知识 用于测量自由基产生，并将尝试开发 EPR应用于生物系统的新技术。 核心B 将为所有项目提供脂质分析技术。 核心C将 测定抗氧化酶蛋白、mRNA和基因拷贝， 将抗氧化酶正义和反义cDNA转染到各种细胞中 线 总之，该计划将利用自然 调查人员在四个相关项目中的互动， 利用四个科学核心，解决一个重要的， 癌症实验疗法的研究不足的方面。

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.