NITRIC OXIDE, HYDROGEN PEROXIDE AND PEROXIDASE IN CANCER CHEMOTHERAPY

描述（由申请人提供）：我们将继续探索 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，包括富含脂质的细胞膜。 我们要发展 氧化和膜策略，以用作增强传统 使其对肿瘤细胞更具选择性。 的假设 需要测试的是，氧化活性介质，特别是信号传导， 分子一氧化氮，可用于治疗优势。 我们的初步 有证据表明，一氧化氮增强了蒽环类药物化疗。 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， 确定该策略是否具有潜在的选择性。 在相关研究中，我们 已经发现H2 O2导致人类白血病细胞凋亡，它可能是 由过氧化物酶介导。 H2 O2来源于细胞内氧化反应， 而来自肿瘤细胞膜脂质的自由基可能起着 在癌症化疗药物的机制中起中心作用， 不同的目标。 在我们的研究中，膜活性和DNA活性药物将被 比较了 敏感/耐药细胞系对将用于探索 过氧化和细胞毒性的关系。 动力学和浓度 每个过氧化事件与即刻细胞毒性的关系， 将测定克隆形成存活率。 氧化的操纵 易感性将使用抗氧化酶的转染进行， 谷胱甘肽耗竭和抗氧化剂。 膜改性模型， 所述细胞可富含各种类型的多不饱和脂肪酸， 从而增加它们对过氧化反应的敏感性， 在一些研究中，它放大了其他方法无法检测到的事件。 的理解 这些调节剂或介质可以提供一个强大的新策略， 抗癌化疗，特别是作为沿着与传统的 细胞毒性癌症化疗。 将继续研究临床背景，但 被迫 研究结果可能会导致设计创新的方法， 实验性地操纵自由基事件以增加 用于肿瘤细胞或克服耐药性的药剂。

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.