OXYGEN AND LIGHT DEPENDENCY OF PHOTODYNAMIC THERAPY

本项目的长期目标是阐明 光动力疗法（PDT）中的氧气，希望改善 治疗实体瘤。 这种竞争性的续期申请仍在继续 在这条道路上。我们已经建立了与光敏剂 Photofrin，PDT可以是自限性的，由于氧耗尽引起的 血管损伤 最近，组织中氧的光化学消耗 通过产生细胞毒性氧物质， 额外限制。 本建议涉及PDT的这一方面。 我们 将研究通过降低光传输速率的建议， 可以减少这种氧消耗，从而提高效率 的治疗。 我们假设，对于某些疾病， 速率降低将充分提高PDT效率， 减少总通量，因此不会过度延长治疗时间。 这可能最终允许以较低的功率和 技术上简化的光源。 我们认为有可能 在完全缓解率为 提高治愈率。 我们进一步 假设这种方法不会对所有情况都有益， 并且可能对某些人有害。 最后，我们假设这种光 递送修饰将影响血管和直接肿瘤细胞 应答 本项目将试图证实这些假设， 临床前和/或临床上。 我们将专注于光敏化 目前临床使用的化合物，即，Photofrin，delta- 氨基乙酰丙酸（ALA）、锡黄嘌呤（SnET 2）和焦脱镁叶绿酸 （HPPH）。 目的1将确定是否采用低注量率制度， 增加PDT效率至达到肿瘤效应的程度， 在相同或更短的治疗时间内，至少等于高注量率治疗 次 将根据数学模型选择通量率， 在组织中提供3/O/2和1/O/2的时间依赖性浓度。 AIM 2将尝试验证PDT氧消耗的模型预测 通过在光照之前、期间和之后直接测量组织pO/2 治疗，检查注量率对药物光漂白的影响， 定义对肿瘤细胞和/或脉管系统的影响。 AIM 3将确定临床光敏剂组织浓度， 薄、中、厚病变患者的光衰减 基底细胞癌、卡波西肉瘤、皮肤T细胞淋巴瘤和 复发性/转移性乳腺癌。 这些数据将用于 数学模型来预测将导致的注量率修改 在不同的肿瘤pO/2水平。 预测将通过直接验证 pO/2测量和治疗方案将被设计为测试我们的 所述假设，即，我们可以取得更大的成就，或者至少 与当前高通量率相当的有效性和选择性 治疗，但总通量较低，没有实质性增加 在治疗时间。

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.