MECHANISMS OF PDT INDUCED AND INHERENT RESISTANCE

PDT 诱导机制和固有抵抗

• 批准号: 6102339
• 负责人: GURMIT SINGH
• 金额: $ 17.07万
• 依托单位: HEALTHONE ALLIANCE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102339
• 关键词: DNA damage; DNA repair; adenocarcinoma; athymic mouse; bladder neoplasm; carcinoma; cell cycle; colon neoplasms; cytotoxicity; digital imaging; drug screening /evaluation; fluorescence microscopy; fluorimetry; glioblastoma multiforme; hexokinase; laboratory mouse; mitochondria; neoplasm /cancer photoradiation therapy; neuroblastoma; nonhuman therapy evaluation; oxidative stress; photosensitizing agents; phthalocyanin; porphyrins; radiation resistance; statistics /biometry

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.

本研究的总体目标是：（a）阐明 光动力疗法通过各种途径诱导抗性的机制 光敏剂;（B）研究导致 不同程度的固有敏感性，光动力治疗， 各种人类肿瘤 本文的研究重点基于以下基本假设：（1） 肿瘤细胞对PDT耐药性的诱导依赖于 细胞改变压力信号的能力。 (2)固有的 调节PDT介导的氧化应激。 (3)的 具有独特细胞内分布的光敏剂的组合 可协同PDT诱导的光毒性。 它还将确保 异质性肿瘤对多种细胞内靶点的反应性。 该项目包括几组实验： 光敏剂细胞/细胞内定位的表征 在体外亲本和PDT诱导抗性变体中;（ii）评估 PDT诱导的光细胞毒性的亚细胞靶点在父母和 体外耐药变异;（iii）检查 PDT介导的细胞反应性，特别是 PDT诱导的损伤的恢复，包括DNA修复途径;（iv） 光动力疗法的作用研究 分子伴侣对PDT诱导的人肿瘤细胞氧化应激的影响; 及（vii）研究受限制的土地的重要性 己糖激酶 体外PDT诱导的耐药变异体的选择是预期的 以放大生物化学或其他细胞内变化， 抵抗。 这一点，以及交叉耐药性之间的程度， 光敏剂有望提供线索， 光敏剂在体外的作用。