PDT--MECHANISMS AND STRATEGIES FOR OPTIMIZATION

PDT--优化机制和策略

• 批准号: 6497740
• 负责人: ALLAN R OSEROFF
• 金额: $ 166.13万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497740
• 关键词: drug screening /evaluation; neoplasm /cancer pharmacology; neoplasm /cancer photoradiation therapy; pharmacokinetics; photochemistry; photosensitizing agents

The overall goals of the Program Project are to gain an increased understanding of the mechanisms of photodynamic therapy (PDT) and to optimize treatment parameters. This will be achieved through the following individual research projects: 1. New, congeneric series of photosensitizers will be prepared and characterized, in order to elucidate those parameters which are important for optimal activity and those which are irrelevant. Quantitative data will be obtained which allow use of multi-dimensional QSAR models, and the predictive value of these models will be examined. The relationship between effective sensitizers and their ability to bind to specific intracellular sites will be examined. 2. The kinetics and tissue distributions of certain cytokines which are induced in vivo by PDT via oxidative stress mechanisms will be explored. The hypotheses that these cytokines can, at least in part, account for the immunopotentiating as well as immunosuppressive effects of PDT will be examined. 3. The questions of whether intracellular binding sites of effective photosensitizers are primarily mitochondrial and if the peripheral benzopdiazepine receptor in this organelle is important in sensitizer binding will be explored. The hypothesis that mitochondrial and PBR- associated sensitizers are important in inducing photodamage and the physiological responses which lead to cell death will be explored. 4. Surrogate variables which will provide real-time and short-term information on the underlying mechanistic processes and probably outcomes in clinical PDT and permit tailoring of the therapy to individual patients and lesions will be developed. As a general paradigm, light dose and dose rate effects will be explored in ALA-PDT with different ALA application times in basal cell carcinomas and cutaneous lymphomas, with examination of the photochemical and biological processes contributing to differences in efficacy, efficiency and selectivity. The Program will be supported by three important technical Core components and an Administrative Core.

该计划的总体目标是增加 了解光动力疗法（PDT）的机制， 优化治疗参数。这将通过以下方式实现 个别研究项目： 1. 将制备新的同类光敏剂系列， 特征，以阐明这些参数是重要的 用于最佳活动和那些不相关的活动。定量数据 将获得允许使用多维QSAR模型， 这些模型的预测值将被检查。的关系 有效的致敏剂和它们结合特异性 将检查细胞内位点。 2. 某些细胞因子的动力学和组织分布 通过氧化应激机制在体内由PDT诱导， 探讨了假设这些细胞因子可以，至少部分， 解释了免疫增强和免疫抑制作用 将检查PDT。 3. 细胞内结合位点是否有效的问题 光敏剂主要是线粒体，如果外周 该细胞器中的苯并二氮卓受体在致敏剂中是重要的 将探索绑定。假设线粒体和PBR- 相关的敏化剂在诱导光损伤中是重要的， 将探索导致细胞死亡的生理反应。 4. 替代变量将提供实时和短期的 关于潜在的机械过程和可能的结果的信息 在临床光动力疗法，并允许定制的治疗，以个别患者 并会出现病变。作为一般范例，光剂量和剂量 将探讨ALA-PDT中不同ALA应用的速率效应 基底细胞癌和皮肤淋巴瘤的次数，伴检查 光化学和生物过程导致了 在功效、效率和选择性方面。该计划将得到以下方面的支持： 三个重要的技术核心和一个管理核心。