OXYGEN AND LIGHT DEPENDENCY OF PHOTODYNAMIC THERAPY

这个项目的长期目标是阐明 氧在光动力疗法(PDT)中的应用 实体肿瘤的治疗。这一相互竞争的续订申请将继续 在这条路上。我们已经证实，使用光敏剂 PHOTOFRIN，PDT可由于以下原因引起的氧气耗竭而自限 血管受损。近年来，组织中氧气的光化学耗竭 通过产生细胞毒性氧物种已被认为是一种 附加限制。这项提案涉及PDT的这一方面。我们 将研究通过降低光线投递率 这种氧气消耗可以减少，从而提高效率。 关于治疗的问题。我们假设，对于某些疾病情况， 降低费率将充分提高PDT效率，以允许 减少总通量，因此不会不适当地延长治疗时间。 这最终可能允许使用不那么强大的和 技术上简化的光源。我们认为这可能是可能的 在完全应答率为 治疗效果不理想，提高治愈率。我们进一步 假设这种方法并不是对所有条件都有利， 而且可能对某些人有害。最后，我们假设这种光 递送修饰将同时影响血管和直接肿瘤细胞 回应。本项目将尝试证实这些假设 临床前和/或临床上。我们将专注于光敏化 目前临床上使用的化合物，即Photofrin，Delta- 氨基酮丙酸(ALA)、锡黄红蛋白(SnET2)和焦脱镁叶绿酸 (HPPH)。 目标1将确定采用低注量率方案是否安全 提高光动力疗法的效率，以达到在 最少等于高通量处理，在相同或更短的处理下 泰晤士报。注量率的选择将基于一个数学模型，该模型 在组织中提供3/O/2和1/O/2的时间依赖浓度。 目标2将尝试验证PDT氧气耗竭的模型预测 通过直接测量光前、光中和光后的组织Po/2 治疗，考察注量率对药物光漂白和 明确对肿瘤细胞和/或血管系统的影响。 AIM 3将在临床上确定光敏剂组织浓度和 脑膜瘤薄、中、厚病变患者的光衰减 基底细胞癌、卡波西斯肉瘤、皮肤T细胞淋巴瘤和 复发/转移性乳腺癌。这些数据将用于 用于预测将导致的通量率修改的数学模型 在不同的肿瘤组织中，Po/2的水平不同。预测将通过DIRECT PO/2测量和治疗方案将设计用于测试我们的 陈述的假设，即我们可以实现更大的，或者至少 与当前的高注量率相比具有相当的效率和选择性 治疗，但总通量较低，且没有大幅增加 在治疗时间里。

It has been the long-term goal of this project to elucidate the role of oxygen in photodynamic therapy (PDT), with the hope of improving the treatment of solid tumors. This competing renewal application continues on this path. We have established that with the photosensitizer Photofrin, PDT can be self-limiting due to oxygen depletion caused by vascular damage. Recently the photochemical depletion of oxygen in tissue through generation of cytotoxic oxygen species has been suggested as an additional limitation. This proposal deals with this aspect of PDT. We will examine the suggestion that by lowering the rate of light delivery this oxygen depletion can be diminished, leading to increased efficiency of treatment. We hypothesize that for certain disease conditions, fluence rate reductions will increase PDT efficiency sufficiently to allow reductions in total fluence, thus not unduly prolonging treatment time. This may eventually allow light delivery with less powerful and technically simplified light sources. We suggest that it may be possible to increase PT efficacy in cases where the complete response rate is unsatisfactory and to enhance the therapeutic ratio. We further hypothesize that this approach will not be beneficial for all conditions, and may be detrimental for some. Finally, we hypothesize that such light delivery modifications will affect both vascular and direct tumor cell responses. This project will try to confirm these hypotheses both preclinically and/or clinically. We will concentrate on photosensitizing compounds which are in current clinical use, i.e., Photofrin, delta- aminolevulinic acid (ALA), tin etiopurpurin (SnET2) and a pyropheophorbide (HPPH). AIM 1 will determine whether employing low fluence rate regimes can safely increase PDT efficiency to such an extent as to achieve tumor effects at least equal to high fluence-rate treatments, at equal or shorter treatment times. Fluence rates will be chosen based on a mathematical model which provides time dependent concentrations of 3/O/2 and 1/O/2 in the tissue. AIM 2 will try to validate the model predictions of PDT oxygen depletion by direct measurements of tissue pO/2 before, during and after light treatment, examine the effects of fluence rate on drug photobleaching and define the effects upon tumor cells and/or the vasculature. AIM 3 will determine clinically photosensitizer tissue concentrations and light attenuation in patients with thin, intermediate and thick lesions of basal cell carcinoma, Kaposis's sarcoma, cutaneous T cell lymphoma and recurrent/metastatic breast cancer. These data will be used in the mathematical model to predict fluence rate modifications which will result in varying tumor pO/2 levels. Predictions will be validated by direct pO/2 measurements, and treatment protocols will be designed to test our stated hypotheses, i.e., that we can achieve greater, or at least comparable efficacy and selectivity to current high fluence rate therapies, but with lower total fluence and without a substantial increase in treatment time.