Physiological Factors in Hyperthermia

描述（由申请人提供）：应用热作为抗癌主要或辅助治疗继续证明自己是一种临床可行和成功的方式。自20世纪90年代初以来，阳性临床试验结果的数量稳步积累。热烧蚀程序的改进技术也在不断增加。随着各种加热设备和策略的使用越来越多，我们对热疗相关温度梯度的生物学和生理学知识的差距越来越大。进一步的知识差距存在于我们有限的能力，以智能地使用放射治疗或其他辅助剂，如抗血管化合物，以最大限度地提高各种热疗法的抗肿瘤作用。我们已经确定这一缺失的知识是一个很大程度上未被满足的机会，以推进热疗法领域，并显着提高癌症治疗的选择。我们坚信，与热治疗各种恶性肿瘤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，增强临床多模式治疗的能力。由于这项工作的复杂性和多学科性，首席研究员在阿肯色大学医学科学学院组建了一个由肿瘤放射生物学、生理学、工程学和物理学专家组成的新团队。小鼠和人类的癌细胞系将在小鼠体内生长。利用这些肿瘤模型，我们旨在确定常规热疗诱导的再氧化模式，以及诱导肿瘤组织血管热耐受性的机制和潜在益处。此外，研究人员还将对新型抗血管药物三氧化二砷（ATO）和金纳米颗粒结合的肿瘤坏死因子-1 （pt - cac - tnf）的损伤模式和肿瘤组织在严重加热后的再氧化进行表征。随后，我们将设计精确的热、抗血管药物和放射治疗组合序列，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)将肿瘤组织暴露在轻度高温下可以改善肿瘤的氧合；(2)严重的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中，但它增加了亚致命治疗区域的氧合，从而加强了放射治疗。我们将使用成熟的细胞生物学和生理测量技术，以及先进的非侵入性成像和热应用与先进的光学和放射成像和超声。活体显微镜将用于研究生长在窗口室的肿瘤，以纵向研究体内治疗效果的机制。在其他部位生长和治疗的肿瘤将进行详细的免疫化学分析，以阐明对肿瘤血管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，有助于改进热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℃下的累积等效分钟（CEM430C）在传统的热疗应用中通常相当低，但在600℃热消融探针的尖端，CEM430C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变化，这取决于正在研究的组织中的确切位置。肿瘤的血流量和氧合在肿瘤的某些区域明显增加。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.