MEMBRANE FREE RADICALS IN PHOTODYNAMIC CANCER THERAPY

描述（由申请人提供）：许多目前的治疗方法， 癌症，例如光动力疗法（PDT），中含有氧化成分 他们的行动机制。 我们对一氧化氮的初步研究 谷胱甘肽表明，它们能够提供实质性保护， 细胞免受PDT的氧化损伤。 一个经常被忽视的方面， 氧化物是它作为链断裂抗氧化剂的能力。 我们假设 在低浓度下，一氧化氮将作为抗氧化剂， PDT在肿瘤细胞中的有效性或保护正常细胞免受 但在较高浓度下，它将是一种促氧化剂。 PDT 将脂质氢过氧化物引入细胞膜。 抗氧化酶， 磷脂氢过氧化物谷胱甘肽过氧化物酶（PhGPx）需要谷胱甘肽 作为辅因子，是一种重要的酶， 膜中的氢过氧化物。 我们已经发现，PhGPx的调节， 细胞将改变细胞对PDT的反应。 Glucosamine提供了 减少从细胞和组织中去除过量过氧化物所需的当量 谷胱甘肽过氧化物酶家族的酶。 此外，均衡 由谷胱甘肽二硫化物/谷胱甘肽对组成的系统被认为 在控制细胞和组织的氧化还原状态中起核心作用。 因此我们 假设细胞对癌症治疗方案的反应依赖于 氧化机制是由细胞或组织的氧化还原状态决定的 以及其控制氧化还原状态的能力。 这项研究的目的是 是为了确定一氧化氮，PhGPx和 谷胱甘肽对PDT的影响 此外，我们提出的研究谷胱甘肽 系统是独一无二的，因为这些研究将是第一次努力，使一个 细胞氧化还原电位的定量估计，并将其与 抗癌治疗的结果。

DESCRIPTION (provided by applicant): Many of the current treatments of cancer, such as photodynamic therapy (PDT), have an oxidative component in their mechanism of action. Our initial studies with nitric oxide and glutathione indicate that they are able to provide substantial protection of cells from the oxidative insult of PDT. An often-overlooked aspect of nitric oxide is its ability to serve as a chain-breaking antioxidant. We hypothesize that at low concentrations nitric oxide will serve as an antioxidant, blunting the effectiveness of PDT in tumor cells or protecting normal cells from damage; however at higher concentrations it will be a pro-oxidant. PDT introduces lipid hydroperoxides into cell membranes. The antioxidant enzyme, phospholipid-hydroperoxide glutathione peroxidase (PhGPx) requires glutathione as a cofactor and is an important enzyme for the removal of these hydroperoxides in the membrane. We have found that modulation of PhGPx in cells will alter the response of cells to PDT. Glutathione provides the reducing equivalents needed to remove excess peroxide from cells and tissues by the glutathione peroxidase family of enzymes. In addition, the equilibrium system composed of the glutathione disulfide/glutathione couple is thought to be central in governing the redox status of cells and tissue. Thus, we hypothesize that the response of cells to cancer treatment protocols that rely on oxidative mechanisms is determined by the redox state of the cell or tissue and its ability to control redox status. The goals of this proposed research are to determine the effects and relationships of nitric oxide, PhGPx and glutathione on PDT. In addition our proposed studies on the glutathione system are unique, as these studies will be the first effort to make a quantitative estimate of cellular redox potential and relate this to an outcome of an anti-cancer therapy.