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)：应用热疗作为抗癌的主要或辅助治疗，继续证明自己是一种临床上可行和成功的治疗方法。自20世纪90年代初以来，阳性临床试验结果的数量一直在稳步积累。也有越来越多的改进技术用于热消融手术。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也越来越大。我们在智能地使用放射疗法或其他辅助剂(如抗血管化合物)以最大限度地发挥各种热疗的抗肿瘤效果方面的能力有限，存在着进一步的知识差距。我们已经确认，这一缺失的知识是一个在很大程度上没有得到满足的机会，可以推动热疗领域的发展，显著提高癌症治疗方案的选择。我们坚信，与应用热疗治疗各种恶性肿瘤相关的详细的生物学和生理学研究将通过提供科学验证的理论基础，使临床多模式治疗成为可能。由于这项工作的复杂性和多学科性质，首席研究员在阿肯色医学大学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团队。小鼠和人类的癌细胞株将在小鼠体内生长。利用这些肿瘤模型，我们的目标是确定传统热疗诱导的复氧模式，以及诱导肿瘤组织血管耐热的机制和潜在的好处。还将研究在添加和不添加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-CAU-TNF)的情况下，肿瘤组织在剧烈加热后的损伤模式和复氧情况。随后，我们将设计组合热、抗血管药物和放射治疗的精确序列，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)肿瘤组织暴露在温和的高温下可以改善肿瘤的氧合作用，(2)严重加热对肿瘤的不同部位是细胞毒的，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，从而加强了放射治疗。我们将使用细胞生物学和生理测量技术方面的成熟方法，以及先进的光学和放射成像仪和超声波的尖端非侵入性成像和热应用。活体显微镜将用于研究在窗腔中生长的肿瘤，以纵向研究体内治疗效果的机制。在其他地方生长和治疗的肿瘤将通过详细的免疫化学分析进行研究，以阐明对肿瘤血管稳定性和成分的影响。所获得的数据将具有科学价值和临床实用价值，有助于完善在热疗和放射治疗领域进行有效转化研究的可能性。这项工作的主要重点是确定热疗和放射治疗相结合的理论基础，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，虽然在传统热疗应用中，430C的累积当量分钟(CEM430C)通常相当低，但在600C热消融探头的尖端，CEM 430C可以高出几个数量级，但我们在这两种情况下都观察到了肿瘤的共同生物学变化，这取决于正在研究的组织中的确切位置。肿瘤某些区域的血流量和氧合显著增加。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，以及它可能如何影响患者对其他应用疗法的反应。