HEAT AND RADIATION EFFECTS ON TUMOR MICROCIRCULATION

描述：（改编自研究者摘要）标识 肿瘤缺氧的原因很重要，因为缺氧会导致 对辐射和一些药物的抵抗力;它诱导产生 血管生成因子;并可能增加转移潜力。整体 这个项目的目标是定量地确定肿瘤 氧合取决于氧的输送和消耗， 信息，以确定控制肿瘤缺氧的有效方法。 这个小组以前的工作集中在慢性缺氧上。在这里，急性 缺氧也将进行调查，目的是确定什么 部分肿瘤是慢性或急性缺氧的， 急性缺氧，以确定时间尺度是什么，在条件下， 正常和变化的氧气供应和需求。具体目标1、 大鼠背侧皮瓣肿瘤血管的三维分布 将使用显微镜测定窗室制剂 磁共振成像和连续组织学重建。 将使用活体显微镜和O2微电极测量 血流和血管周围O2水平的时间变化， O2消耗速率会发生时间变化。理论模型 将用于预测慢性和 短暂缺氧基于这些观察。具体目标的目标 2是检查几种方法的有效性， 肿瘤氧合先前的建模研究预测， O2消耗率和/或血液O2含量的增加是最重要的 有效因此，我们将确定如何减少O2消耗量 （由体温过低、高血糖、鱼藤酮或甲硝唑引起）或 血液中O2含量增加（使用Carbogen、100% O2或高压O2） 单独或联合使用会改变微血管功能，02 消耗和氧化。含血红蛋白的 脂质体作为O2载体将被研究，因为一些肿瘤血管 观察到携带血浆但不携带红细胞。据报道， 以减少间歇性吹送流量，并将测试其效果， 不含碳水化合物我们还将研究降低肿瘤p02的方法， 符合目前的战略，以利用这种条件与缺氧 细胞毒素我们将测试的策略将集中在方法上， 增加O2消耗率并降低肿瘤血流量。在特定 目标3，将进一步测试改变肿瘤氧合的策略 用极谱法测量侧腹制剂中的肿瘤氧合 以及通过肿瘤照射后的再生长延迟实验。改进 定量了解肿瘤氧合的决定因素， 修改02输送和消耗的方法的基础应形成 成功控制肿瘤缺氧。拟议的研究将采用 实验和理论方法的独特结合， 专业知识，以获得这样的了解肿瘤氧合及其 微循环水平的改变。

DESCRIPTION: (adapted from the investigator's abstract) Identification of causes of tumor hypoxia is important because hypoxia causes resistance to radiation and a number of drugs; it induces production of angiogenic factors; and may increase metastatic potential. The overall goal of this project is to quantitatively establish how tumor oxygenation depends on oxygen delivery and consumption, and to use this information to identify effective methods for controlling tumor hypoxia. Prior work by this group has focused on chronic hypoxia. Here, acute hypoxia will also be investigated with the goal of determining what fractions of tumor are either chronically or acutely hypoxic and, for acute hypoxia, to determine what the time scales are, under conditions of normal and modified oxygen supply and demand. In Specific Aim 1, three dimensional vascular arrangements in tumors in rat dorsal flap window chamber preparations will be determined using microscopic magnetic resonance imaging and serial histologic reconstruction. Intravital microscopy and O2 microelectrodes will be used to measure temporal changes in blood flow and perivascular 02 levels and if temporal variations in 02 consumption rates occur. Theoretical models will be used to predict the extent and character of chronic and transient hypoxia based on these observations. The goal of Specific Aim 2 is to examine the effectiveness of several approaches for modifying tumor oxygenation. Previous modeling studies predict that reduction in 02 consumption rate and/or increase in blood 02 content are most effective. Thus, we will determine how reduction in 02 consumption (induced by hypothermia, hyperglycemia, rotenone or metronidazole) or increase in blood 02 content (using carbogen, 100% 02, or hyperbaric 02) alone or in combination will alter microvascular function, 02 consumption, and oxygenation. The effects of hemoglobin-containing liposomes as 02 carriers will be investigated, since some tumor vessels are observed to carry plasma but not red cells. Nicotinamide is reported to reduce intermittent blow flow, and its effects will be tested, with and without carbogen. We will also study means to reduce tumor p02, in line with current strategies to exploit such conditions with hypoxic cytotoxins. Strategies that we will test will focus on methods to increase 02 consumption rate and decrease tumor blood flow. In Specific Aim 3, strategies for modifying tumor oxygenation will be further tested by polarographic measurements of tumor oxygenation in flank preparations and by regrowth delay experiments following tumor irradiation. Improved quantitative understanding of the determinants of tumor oxygenation and of methods to modify 02 delivery and consumption should form a basis for successful control of tumor hypoxia. The proposed studies will employ a unique combination of experimental and theoretical methods and expertise to gain such understanding of tumor oxygenation and its modification at the microcirculatory level.