Oxygen and photosensitizer levels in photodynamic therapy of head and neck tumors

描述（由申请人提供）：光动力疗法（PDT）是一种使用光敏剂和光杀死细胞的治疗方式。在标准的光动力学反应中，同时存在的氧气也是组织损伤发生所必需的。该项目集中在PDT治疗头颈部癌前粘膜病变的I期试验，主要目的是确定口服ALA（Levulan）-PDT的毒性。在高达30%的病例中，头颈部发育不良与随后进展为浸润性癌的风险相关。与治疗癌前头颈部癌症的替代方法相比，PDT提供了微创、耗时少、保留器官、对患病组织具有选择性以及易于重复治疗的可能优势。临床试验的次要目的是评估患者患病和正常头颈组织中的光敏剂和氧浓度，因为PDT的选择性和疗效部分取决于组织光敏剂和氧水平。在啮齿动物口腔癌和头颈部人类肿瘤异种移植物的临床前研究中，将评价光敏剂和氧浓度之间的肿瘤内和肿瘤间关系，并研究氧和光敏剂分布的异质性对治疗结果的影响。将使用无创体内光谱法进行研究，以测量组织氧和光敏剂含量。此外，将使用免疫组织化学和/或荧光显微镜技术在临床前组织中测量这些参数的显微镜分布。我们的建议的目的可以概括如下：目的1：完成PDT与ALA（Levulan）的头和颈部癌前肿瘤的I期试验。问题1A：ALA-PDT的毒性和最大耐受剂量是多少？目的2：从I期试验中测量头部和颈部组织中PDT前后的氧水平和光敏剂含量。问题2A：PDT如何影响病变组织与正常组织中的组织氧和光敏剂水平？目标3：定义和评价啮齿动物肿瘤模型中组织光敏剂和氧含量的宏观和微观异质性的治疗相关性。问题3A：氧和光敏剂浓度的不均匀性如何影响治疗结果？问题3B：氧和光敏剂水平的宏观不均匀性是否是潜在的微观不均匀性的指标？问题3C：氧和光敏剂的分布在空间上是如何相关的？

DESCRIPTION (provided by applicant): Photodynamic therapy (PDT) is a treatment modality that uses a photosensitizing agent and light to kill cells. In standard photodynamic reactions the simultaneous presence of oxygen is also required for tissue damage to occur. This project centers on a Phase I trial of PDT for pre-malignant mucosal lesions of the head and neck, with the primary goal of defining the toxicities of orally-administered ALA (Levulan)-PDT. Dysplasia of the head and neck is associated with subsequent risk of progression to invasive carcinoma in up to 30% of cases. Compared to alternative methods of treating pre-malignant head and neck cancer, PDT offers the possible advantages of being minimally invasive, less time consuming, organ preserving, selective for diseased tissue, and amenable to repeat treatment. A secondary aim of the clinical trial will be to evaluate photosensitizer and oxygen concentrations in the diseased and normal head and neck tissues of patients because the selectivity and efficacy of PDT depends in part on tissue photosensitizer and oxygen levels. In pre-clinical studies of rodent oral cancer and head and neck human tumor xenografts, the intra-tumor and inter-tumor relationships between photosensitizer and oxygen concentrations will be evaluated, and the effect of heterogeneities in oxygen and photosensitizer distributions on therapeutic outcome will be investigated. Studies will be conducted using noninvasive in vivo spectroscopy to measure tissue oxygen and photosensitizer content. Additionally, the microscopic distributions of these parameters will be measured in pre-clinical tissues using immunohistochemical and/or fluorescence microscopic techniques. The aims of our proposal can be summarized as follows: Aim 1: To complete a Phase I trial of PDT with ALA (Levulan) for pre-malignant tumors of the head and neck. Question 1A: What are the toxicities and maximally tolerated dose of ALA-PDT? Aim 2: To measure pre- and post-PDT levels of oxygen and photosensitizer content in head and neck tissues from the Phase I trial. Question 2A: How does PDT affect tissue oxygen and photosensitizer levels in diseased vs. normal tissue? Aim 3: To define and evaluate the therapeutic relevance of macroscopic and microscopic heterogeneities in tissue photosensitizer and oxygen content in rodent tumor models. Question 3A: How do heterogeneities in oxygen and photosensitizer concentrations affect therapeutic outcome? Question 3B: Are macroscopic heterogeneities in oxygen and photosensitizer levels measures of underlying microscopic heterogeneities? Question 3C: How are distributions of oxygen and photosensitizer spatially related?