Project 4: Understanding and Optimizing Vascular Response to

摘要 项目四： 光动力疗法（PDT）可在照明期间产生局部缺血，导致治疗限制性的 缺氧缺血和缺氧可以限制直接细胞毒性，以及改变PDT反应的其他方面， 例如，对信号转导和免疫反应的影响已被证明。因此，肿瘤 照明期间的微环境对PDT响应的多个方面至关重要，这些方面共同决定 疗效胸膜PDT（p-PDT）治疗间皮瘤临床试验的初步数据检测 在光照期间改变反应的局部缺血。P-PDT并不能控制局部复发，尽管改善了局部复发。 存活，这可能表明微环境诱导的细胞毒性限制。为了达成一致，我们测量了 在照明过程中，总血红蛋白和氧合血红蛋白的局部浓度分别降低 表明治疗诱导的缺血和缺氧。此外，在PDT中增加手术可以改变 微环境，因为手术诱导促炎性和血管活性物质的全身释放， 细胞因子特别是，我们发现手术诱导的IL-6与胸部缺氧的发展相关， 在随后的照明过程中。根据这些数据，我们假设血管对 间皮瘤累及胸腔的术中PDT将决定治疗结果。研究将 作为我们的II期p-PDT试验的一部分，以及在胸内和 术中PDT。目的1明确间皮瘤患者的血管微环境， 评价手术引起的血流动力学变化的临床相关性。我们的目标包括评估 间皮瘤的血管形成;测量PDT诱导的血管功能变化;以及 这些因素如何与局部控制，毒性和生存的p-PDT的定义。目标2将 确定血管反应如何影响小鼠模型中术中PDT的功效 间皮瘤该目的将定义胸部照明和手术诱导的细胞因子的后果 血管对PDT反应的信号传导，这种损伤对结果的重要性，以及调节血管对PDT反应的可能性。 p-PDT期间的血管反应，以获得治疗益处。

Abstract Project 4: Photodynamic therapy (PDT) can produce local ischemia during illumination that leads to treatment-limiting hypoxia. Ischemia and hypoxia can limit direct cytotoxicity, as well as alter other aspects of PDT response, for example, effects on signal transduction and immune responses have been documented. Thus, tumor microenvironment during illumination is critical to multiple facets of PDT response that collectively determine therapeutic efficacy. Preliminary data from our clinical trial of pleural-PDT (p-PDT) for mesothelioma detect response-altering ischemia during illumination. P-PDT did not control local recurrence, despite improvement in survival, which could indicate microenvironment-induced limitations in cytotoxicity. In agreement, we measured decreases in local concentrations of total and oxygenated hemoglobin during illumination, respectively indicating treatment-induced ischemia and hypoxia. Furthermore, the addition of surgery to PDT could alter microenvironment because surgery induces the systemic release of pro-inflammatory and vasoactive cytokines. In particular, we found IL-6 induction by surgery to correlate with hypoxia development in thoracic tissues during their subsequent illumination. From these data, we hypothesize that vascular response to intraoperative PDT of the mesothelioma-involved thoracic cavity will determine treatment outcome. Studies will be performed as a part of our Phase II, p-PDT trial, as well as in murine models of intrathoracic and intraoperative PDT. Aim 1 will ascertain the vascular microenvironment of mesothelioma in patients and evaluate the clinical relevance of procedure-induced hemodynamic change. Our goals include assessment of the vascularization of mesothelioma; measurement of PDT-induced changes in vascular function; and definition of how these factors correlate with local control, toxicities, and survival in p-PDT. Aim 2 will determine how vascular responses contribute to the efficacy of intraoperative PDT in murine models of mesothelioma. This Aim will define the consequences of thoracic illumination and surgery-induced cytokine signaling on vessel response to PDT, the importance of this damage to outcome, and the potential to modulate vascular response during p-PDT for therapeutic benefit.