Physiological Factors in Hyperthermia

热疗的生理因素

• 批准号: 7911121
• 负责人: Robert James Griffin
• 金额: $ 30.18万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911121
• 关键词: Adjuvant; Affect; Area; Arkansas; Arsenic Trioxide; Binding; Biological; Biology; Blood Vessels; Blood flow; Cancer cell line; Carbogen Breathing; Cellular biology; Clinical; Clinical Trials; Complex; Data; Devices; Engineering; Fever; Goals; Gold; Heating; High temperature of physical object; Human; Image; Injury; Intervention; Investigation; Knowledge; Location; Malignant Neoplasms; Measurement; Medical; Methods; Modality; Modeling; Molecular; Mus; Nature; Normal tissue morphology; Optics; Outcome; Patients; Pattern; Physics; Physiological; Physiology; Principal Investigator; Procedures; Radiation; Radiation therapy; Radiobiology; Recording of previous events; Recurrence; Research; Research Activity; Science; Solid Neoplasm; Techniques; Technology; Temperature; Therapeutic; Thermal Ablation Therapy; Tissues; Translational Research; Treatment Efficacy; Tumor Biology; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor Oxygenation; Tumor Tissue; Ultrasonography; Universities; Work; cancer therapy; chemotherapy; clinical application; cytotoxic; density; design; empowered; hyperthermia treatment; improved; in vivo; intravital microscopy; nanoparticle; novel; programs; response; success; treatment effect; tumor; tumor eradication; tumor xenograft

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.

描述（由申请人提供）：将热量作为抗癌药或辅助治疗的应用继续证明自己是一种临床可行且成功的模态。自1990年代初以来，积极的临床试验结果的数量一直稳步积累。用于热烧蚀程序的改进技术也越来越多。随着各种加热设备和策略的越来越多的用途，我们的知识与热治疗相关温度梯度的生物学和生理学有关。知识的进一步差距是我们有限的智能使用放射疗法或其他辅助剂（例如抗血管化合物）的能力有限，以最大程度地提高各种热疗法的抗肿瘤作用。我们已经将这种缺失的知识确定为进步热疗法领域并显着增强癌症治疗选择的机会。我们的信念是，与热量在各种恶性肿瘤中应用有关的详细生物学和生理研究将通过提供科学验证的基本原理来增强临床多模式疗法的能力。由于这项工作的复杂和多学科的性质，首席研究人员已在阿肯色大学的医学科学大学组成了一支新的肿瘤辐射生物学，生理，工程和物理学专家团队。小鼠将生长鼠和人类癌细胞系。使用这些肿瘤模型，我们旨在鉴定传统高温和机制引起的重氧模式，以及诱导肿瘤组织中血管耐糖体的潜在益处。在有或不加入新型抗血管剂三氧化物（ATO）和金纳米粒子结合的肿瘤坏死因子1（PT-CAU-TNF）的情况下，有或没有添加新型抗血管剂三氧化物（ATO）（ATO）（PT-CAU-TNF），肿瘤组织的损伤模式和肿瘤组织的重聚。随后，我们将设计组合热量，抗血管剂和放射治疗的精确序列，以获得最佳的抗肿瘤作用。这项工作的中心假设是两个折叠：（1）肿瘤组织暴露于轻微的高温过高可改善肿瘤的氧合性，（2）严重的加热对肿瘤的不同部分是细胞毒性的，尤其是抗血管治疗，但通过抗血管治疗增加了细胞质处理的区域中的氧合作用，从而增加了细胞处理的受到增强的放射治疗。我们将在细胞生物学和生理测量技术中使用良好的方法，以及具有先进的光学和射线照相成像仪和超声检查的最先进的非侵入性成像和热量应用。插入显微镜将用于研究在窗室中生长的肿瘤，以纵向研究体内治疗作用的机理。将研究在其他位置生长和治疗的肿瘤，并进行详细的免疫化学分析，以阐明对肿瘤脉管系统稳定性和组成的影响。获得的数据将是科学有价值的，而且在临床上是实用的，有助于完善在热和放射疗法领域有效翻译研究的可能性。这项工作的主要重点是定义将热疗法与放射治疗相结合的基本原理，并详细说明肿瘤和正常组织对传统高温温度或热消融的反应。这项工作的一个反复出现的主题是，虽然在传统高温应用应用中，通常在430c（CEM430C）的累积等效分钟通常很低，但CEM 430c可以在600℃的热消融探针的尖端中更高几个数量级，但我们在两种情况下都会在肿瘤中观察到在两种情况下在肿瘤中的常见生物学变化，具体取决于在整个组织中的确切位置。在肿瘤的某些区域中，肿瘤血流和氧合作用显着增加。我们的主要重点是定义发生这种情况的地方，为什么会发生这种情况以及如何影响患者对其他应用疗法的反应。