MECHANISMS OF PDT INDUCED AND INHERENT RESISTANCE

这项研究的整体目标是：(A)澄清 光动力疗法诱导抗性的机制(S) 光敏剂和；。(B)调查导致 不同程度的人对光动力疗法的固有敏感性 各种人类肿瘤。 研究的重点是基于以下主要假设：(1) 肿瘤细胞对光动力疗法耐药的诱导依赖于 细胞改变应力信号的能力。(2)固有的 调节PDT介导的氧化应激。(3) 具有独特细胞内分布的光敏剂组合 可能对PDT诱导的光毒性有协同作用。它还将确保 异种肿瘤对多种细胞内靶点的反应性。 该项目包括几组实验：(I) 光敏剂细胞/细胞内定位的表征 亲本和PDT诱导的抗性变异体的体外研究；(Ii)评估 光动力诱导的亲本细胞光细胞毒作用亚细胞靶点的研究 体外耐药变异体；(Iii)检测参与的途径 PDT介导的细胞反应性，特别是 光动力损伤的修复，包括DNA修复途径；(Iv) 光动力疗法诱导细胞作用的研究 伴侣对光动力诱导的人肿瘤细胞氧化应激的影响； 和(Vii)检查线粒体结合的重要性 己糖激酶类。 体外筛选PDT诱导的抗性变异体是可望的 放大相关的生化或其他细胞内变化 带着抵抗。这一点，以及两者之间的交叉阻力程度 光敏剂有望提供有关其发病机制的线索。 光敏剂的体外作用。

The overall objectives of this study are: (a) to elucidate the mechanism(s) of photodynamic therapy induced resistance by various photosensitizers and; (b) to investigate factors responsible for the varying degree of inherent sensitivity to photodynamic therapy in various human tumors. The research focus is based on the following primary hypotheses: (1) That the induction of resistance to PDT in tumor cells is dependent on the ability of cells to alter the stress signals. (2) The inherent modulate the oxidative stress mediated by PDT. (3) That the combination of photosensitizers with unique intracellular distribution may synergize the PDT induced phototoxicity. It would also ensure the responsiveness of heterogenous tumors to multiple intracellular targets. The project comprises several groups of experiments: (i) characterization of photosensitizer cellular/intracellular localization in parent and PDT- induced resistant variants in vitro; (ii) assessment of subcellular targets of PDT induced photocytotoxicity in parent and resistant variants in vitro; (iii) examination of pathways involved in PDT mediated responsiveness of cells, in particular the pathways for recovery of PDT - induced damage including DNA repair pathways; (iv) investigation of the role of PDT induced cell examination of the role of chaperones on PDT - induced oxidative stress in human tumor cells; and (vii) examination of the importance of mitochondrial-bound hexokinases. The selection of in vitro PDT - induced resistant variants is expected to amplify the biochemical or other intracellular changes associated with resistance. This, and the degree of cross-resistance between the photosensitizers are expected to provide clues as to the mechanisms of action of photosensitizers in vitro.