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

头颈肿瘤光动力治疗中的氧气和光敏剂水平

基本信息

批准号：
7788863
负责人：
Theresa M Busch
金额：
$ 34.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7788863
关键词：
Affect Area Carcinoma Carcinoma in Situ Characteristics Clinical Clinical Trials Disease Dose Dysplasia Erythroplasia Fluorescence Fractionation Goals Head and Neck Cancer Head and Neck Neoplasms Head and neck structure Heterogeneity Human Ionizing radiation Larynx Lesion Levulan Light Lighting Malignant Neoplasms Maximum Tolerated Dose Measurement Measures Methods Microscopic Modality Modeling Neck Disorder Normal tissue morphology Operative Surgical Procedures Optics Oral cavity Organ Outcome Oxygen Oxygen Consumption Patients Pharmaceutical Preparations Pharyngeal structure Phase I Clinical Trials Photochemotherapy Photosensitizing Agents Premalignant Process Property Protocols documentation Reaction Risk Rodent Rodent Model Severe dysplasia Spectrum Analysis Superficial Lesion Techniques Therapeutic Time Tissues Toxic effect Treatment Efficacy Treatment outcome Tumor Tissue absorption base cell killing in vivo insight malignant mouth neoplasm minimally invasive oncology pre-clinical preclinical study public health relevance response tissue oxygenation tumor tumor xenograft

项目摘要

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? PUBLIC HEALTH RELEVANCE: Photodynamic therapy (PDT) is a local light- and drug-based treatment that offers significant potential as a method of treating superficial lesions of pre-malignant disease of the head and neck while causing little toxicity to normal tissues. Compared to the alternatives of surgery or ionizing radiation, PDT offers the possible advantages of being minimally invasive, less time consuming, organ preserving, selective for diseased tissue, and amenable to repeat treatment.

描述（由申请人提供）：光动力疗法（PDT）是一种使用光敏剂和光来杀死细胞的治疗方式。在标准光动力反应中，组织损伤的发生也需要氧气的同时存在。该项目以针对头颈部癌前粘膜病变的 PDT I 期试验为中心，主要目标是确定口服 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。与治疗恶变前头颈癌的其他方法相比，PDT 具有微创、耗时少、器官保存、对病变组织有选择性以及易于重复治疗等可能的优势。该临床试验的第二个目标是评估患者患病和正常头颈部组织中的光敏剂和氧气浓度，因为 PDT 的选择性和疗效部分取决于组织光敏剂和氧气水平。在啮齿类口腔癌和头颈人类肿瘤异种移植物的临床前研究中，将评估光敏剂和氧气浓度之间的肿瘤内和肿瘤间关系，并研究氧气和光敏剂分布的异质性对治疗结果的影响。调查了。研究将使用无创体内光谱来测量组织氧和光敏剂含量。此外，将使用免疫组织化学和/或荧光显微技术在临床前组织中测量这些参数的微观分布。我们提案的目标可概括如下：目标 1：完成 ALA（Levulan）PDT 治疗头颈部癌前肿瘤的 I 期试验。问题 1A：ALA-PDT 的毒性和最大耐受剂量是多少？目标 2：测量 I 期试验中头颈组织中 PDT 前后的氧气水平和光敏剂含量。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：定义和评估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：氧气和光敏剂浓度的异质性如何影响治疗结果？问题 3B：氧和光敏剂水平的宏观异质性是否可以衡量潜在的微观异质性？问题 3C：氧和光敏剂的分布在空间上有何关系？公共健康相关性：光动力疗法 (PDT) 是一种基于局部光和药物的治疗方法，作为治疗头颈部癌前病变浅表病变的方法具有巨大潜力，同时对正常组织几乎没有毒性。与手术或电离辐射的替代方案相比，PDT 具有微创、耗时少、器官保存、对病变组织有选择性以及易于重复治疗等可能的优势。