Physiological Factors in Hyperthermia

描述（由申请人提供）：热作为抗癌主要或辅助治疗的应用继续证明其本身是临床上可行和成功的方式。自20世纪90年代初以来，积极的临床试验结果数量稳步积累。还有一个不断增长的清单，改进技术的热消融程序。随着各种加热设备和策略的使用越来越多，我们对热治疗相关温度梯度的生物学和生理学知识的差距越来越大。知识的进一步差距存在于我们智能地使用放射疗法或其他佐剂（诸如抗血管化合物）以最大化各种热疗法的抗肿瘤效果的有限能力中。我们已经确定，这种缺失的知识在很大程度上是一个未得到满足的机会，以推进热疗法领域，并显着提高癌症治疗的选择。我们相信，与针对各种恶性肿瘤的热应用相关的详细生物学和生理学研究将通过提供科学验证的原理来增强临床多模态治疗。由于这项工作的复杂性和多学科性，主要研究者在阿肯色州大学医学科学部组建了一个新的肿瘤辐射生物学、生理学、工程学和物理学专家小组。鼠和人癌细胞系将在小鼠中生长。使用这些肿瘤模型，我们的目标是确定再氧合模式诱导的常规热疗和机制，以及潜在的好处，诱导血管热耐受性的肿瘤组织。还将表征在添加和不添加新型抗血管剂三氧化二砷（ATO）和金纳米颗粒结合的肿瘤坏死因子-1（Pt-cAu-TNF）的情况下严重加热后肿瘤组织的损伤模式和再氧合。随后，我们将设计精确的组合热，抗血管药物和放射治疗的序列，以获得最佳的抗肿瘤效果。这项工作的中心假设是双重的：（1）肿瘤组织暴露于轻度高温改善了肿瘤氧合，（2）严重加热对肿瘤的不同部分具有细胞毒性，特别是在抗血管治疗的情况下，但它增加了亚致死治疗区域的氧合，从而增强了放射治疗。我们将使用细胞生物学和生理测量技术以及先进的光学和放射成像仪和超声的尖端非侵入性成像和热应用的成熟方法。活体显微镜将用于研究在窗口室中生长的肿瘤，以纵向研究体内治疗效果的机制。将通过详细的免疫化学分析研究在其他位置生长和治疗的肿瘤，以阐明对肿瘤血管系统稳定性和组成的影响。所获得的数据将具有科学价值和临床实用性，有助于改善热疗和放射治疗领域有效转化研究的可能性。这项工作的主要重点是定义热治疗与放射治疗相结合的基本原理，并详细解释肿瘤和正常组织对传统热疗温度或热消融的反应。这项工作的一个反复出现的主题是，虽然在430 C（CEM 430 C）的累积等效分钟数在传统的热疗应用中通常相当低，但CEM 430 C在600 C热消融探针的尖端可以大几个数量级，但我们在两种情况下观察到肿瘤中常见的生物学变化，这取决于正在研究的组织中的确切位置。肿瘤血流和氧合在肿瘤的某些区域显著增加。我们的主要重点是确定这种情况发生在哪里，为什么会发生，以及它如何影响患者对其他应用疗法的反应。

DESCRIPTION (provided by applicant): The application of heat as an anti-cancer primary or adjuvant treatment continues to prove itself as a clinically viable and successful modality. The number of positive clinical trial outcomes has steadily accumulated since the early 1990s. There is also a growing list of improved technology for thermal ablative procedures. With increasing uses of various heating devices and strategies comes an increasing gap in our knowledge pertaining to the biology and physiology of thermal therapy-associated temperature gradients. A further gap in knowledge exists in our limited abilities to intelligently use radiation therapy or other adjuvants such as anti- vascular compounds to maximize the anti-tumor effects of various thermal therapies. We have identified this missing knowledge as a largely unmet opportunity to advance the field of thermal therapy and significantly enhance cancer treatment options. It is our conviction that detailed biological and physiological investigations related to the application of heat against various malignancies will empower clinical multi-modality therapy by supplying scientifically validated rationale. Because of the complex and multi-disciplinary nature of this work, the principal investigator has assembled a new team of experts in tumor radiation biology, physiology, engineering and physics at the University of Arkansas for Medical Sciences. Murine and human cancer cell lines will be grown in mice. Using these tumor models we aim to identify reoxygenation patterns induced by conventional hyperthermia and the mechanisms as well as potential benefits of inducing vascular thermotolerance in tumor tissue. The injury patterns and reoxygenation of tumor tissue after severe heating with and without the addition of the novel anti-vascular agents arsenic trioxide (ATO) and gold-nanoparticle-bound tumor necrosis factor-1 (Pt-cAu-TNF) will also be characterized. Subsequently, we will design precise sequences of combined heat, anti-vascular agents and radiation therapy to obtain optimal anti-tumor effects. The central hypothesis of this work is two-fold: (1) exposure of tumor tissue to mild hyperthermia improves tumor oxygenation and (2) severe heating is cytotoxic to varying portions of the tumor, especially with anti-vascular treatment, yet it increases oxygenation in sub-lethally treated areas thereby enhancing radiation therapy. We will use well established methods in cell biology and physiological measurement techniques as well as cutting-edge non-invasive imaging and heat application with advanced optical and radiographic imagers and ultrasound. Intravital microscopy will be used to study tumors grown in window chambers to longitudinally investigate mechanisms of treatment effects in vivo. Tumors grown and treated in other locations will be studied with detailed immunochemical analysis to elucidate effects on the tumor vasculature stability and composition. The data obtained will be both scientifically valuable and clinically practical, helping to refine the possibilities for effective translational research in the field of thermal and radiation therapy. The main focus of this work is to define the rationale for combining thermal therapy with radiation therapy and explain in detail the response of tumor and normal tissue to traditional hyperthermia temperatures or thermal ablation. A recurring theme of the work is that while the cumulative equivalent minutes at 430C (CEM430C) are usually quite low in traditional hyperthermia applications, the CEM 430C can be several orders of magnitude greater at the tip of a 600C thermal ablation probe yet we observe common biological changes in the tumor in both cases, depending on the exact location in the tissue that is being studied. Tumor blood flow and oxygenation is significantly increased in certain areas of the tumor. Our primary focus is to define where this happens, why this happens and how it may influence patient response to other applied therapies.