NITRIC OXIDE, HYDROGEN PEROXIDE AND PEROXIDASE IN CANCER CHEMOTHERAPY

简介(申请人提供)：我们会继续探索 氧化事件在抗癌药物细胞毒性中的重要性 不同的细胞靶点，包括富含脂质的膜。我们希望发展 氧化和膜策略用作辅助手段，以增强传统 化疗，使其对肿瘤细胞更具选择性。假说 要测试的是氧化活性介质，特别是信号转导 一氧化氮分子，可用于治疗的优势。我们的预赛 有证据表明，一氧化氮可以增强蒽环类药物的化疗效果。 初步研究将在体外进行，以确认最有希望的 药物，以及药物和一氧化氮的最佳时间和浓度 随后在体内使用。我们还将研究培养的心脏细胞以 确定该战略是否具有潜在的选择性。在相关研究中，我们 发现过氧化氢会导致人类白血病细胞的凋亡，而且它可能是 由过氧化物酶介导。细胞内氧化反应产生的过氧化氢， 而来源于肿瘤细胞膜脂质的自由基可能起到了 多种化疗药物在肿瘤机制中的核心作用 不同的目标。在我们的研究中，膜活性药物和DNA活性药物将是 比较一下。将使用敏感/耐药细胞系对来探索 过氧化与细胞毒性的关系。动力学和浓度 每种过氧化事件与即刻细胞毒性和 克隆人的存活将被确定。氧化的操控 敏感性将通过导入抗氧化酶来实现， 谷胱甘肽耗竭和抗氧化剂。一种膜的改性模型 这些细胞可以富含各种类型的多不饱和脂肪酸， 从而增加他们对过氧化事件的易感性，将被使用 在一些研究中，用来放大原本无法检测到的事件。一种理解 这些调节器或调节器可以提供一个强大的新策略 抗癌化疗，特别是作为佐剂与传统的 细胞毒性癌症化疗。将继续研究临床情况，但不会 迫不得已。结果可能会导致设计出创新的方法来 通过实验操纵自由基事件以提高选择性 治疗肿瘤细胞或克服耐药性的药物。

DESCRIPTION (provided by applicant): We will continue to explore the importance of oxidative events in the cytotoxicity of anticancer drugs with different cellular targets including lipid-rich membranes. We wish to develop oxidative and membrane strategies to use as adjuncts to enhance traditional chemotherapy and make it more selective for neoplastic cells. The hypothesis to be tested is that oxidatively active mediators, especially the signaling molecule nitric oxide, can be used to therapeutic advantage. Our preliminary evidence shows that nitric oxide amplifies anthracycline chemotherapy. Initial investigations will be done in vitro to confirm the most promising drugs, and the optimal times and concentrations of drugs and nitric oxide to be used subsequently in vivo. We will also study cultured heart cells to ascertain if the strategy has potential selectivity. In related studies, we have found that H2O2 causes apoptosis in human leukemia cells, and it may be mediated by peroxidase. H2O2 derived from intracellular oxidation reactions, and free radicals derived from lipids of neoplastic cell membranes may play a central role in the mechanism of cancer chemotherapy agents with diverse and distinct targets. In our studies membrane-active and DNA-active drugs will be compared. Sensitive/resistant cell line pairs will be used to explore the relationship of peroxidation and cytotoxicity. The kinetic and concentration relationship of each peroxidative event to immediate cytotoxicity and clonogenic survival will be determined. Manipulation of oxidative susceptibility will be done using transfection of antioxidant enzymes, glutathione depletion, and antioxidants. A membrane modification model by which cells can be enriched with polyunsaturated fatty acids of various types, thereby increasing their susceptibility to peroxidative events, will be used in some studies to amplify events not otherwise detectable. An understanding of these modulators or mediators can provide a powerful new strategy for anticancer chemotherapy especially as adjuvants along with traditional cytotoxic cancer chemotherapy. Clinical contexts will be pursued, but not forced. The results could lead to the design of innovative ways to experimentally manipulate free radical events to increase selectivity of agents for neoplastic cells or overcome resistance.