Physiological Factors in Hyperthermia

热疗的生理因素

• 批准号: 8396555
• 负责人: Robert James Griffin
• 金额: $ 4.77万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396555
• 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; TNF gene; Techniques; Technology; Temperature; Therapeutic; Thermal Ablation Therapy; Tissues; Translational Research; Treatment Efficacy; Tumor Biology; Tumor Necrosis Factor-alpha; 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）：应用热作为抗癌主要或辅助治疗继续证明其是一种临床上可行且成功的方式。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。热消融手术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，我们在与热疗相关的温度梯度的生物学和生理学方面的知识差距越来越大。进一步的知识差距存在于我们智能地使用放射疗法或其他辅助剂（例如抗血管化合物）以最大限度地发挥各种热疗法的抗肿瘤作用的能力有限。我们发现这种缺失的知识在很大程度上是一个未满足的机会，可以推动热疗法领域的发展并显着增强癌症治疗选择。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来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质，主要研究者在阿肯色大学医学科学分校组建了一个由肿瘤放射生物学、生理学、工程和物理学专家组成的新团队。鼠和人类癌细胞系将在小鼠体内培养。使用这些肿瘤模型，我们的目的是确定传统热疗诱导的复氧模式以及在肿瘤组织中诱导血管耐热性的机制以及潜在益处。还将对添加和不添加新型抗血管药物三氧化二砷 (ATO) 和金纳米颗粒结合肿瘤坏死因子-1 (Pt-cAu-TNF) 的情况下剧烈加热后肿瘤组织的损伤模式和再氧合进行表征。随后，我们将设计精确的热疗、抗血管药物和放射治疗组合的顺序，以获得最佳的抗肿瘤效果。这项工作的中心假设有两个：（1）将肿瘤组织暴露于轻度高温下可改善肿瘤氧合；（2）剧烈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，但它会增加亚致死治疗区域的氧合，从而增强放射治疗。我们将使用细胞生物学和生理测量技术中成熟的方法，以及尖端的非侵入性成像和热应用以及先进的光学和放射成像仪和超声波。活体显微镜将用于研究窗室中生长的肿瘤，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来研究在其他位置生长和治疗的肿瘤，以阐明对肿瘤脉管系统稳定性和组成的影响。获得的数据将具有科学价值和临床实用性，有助于提高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法与放射疗法相结合的基本原理，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，虽然在传统热疗应用中 430C (CEM430C) 下的累积等效分钟数通常相当低，但在 600C 热消融探针尖端的 CEM 430C 可能要大几个数量级，但我们在这两种情况下观察到肿瘤中常见的生物学变化，具体取决于正在研究的组织中的确切位置。肿瘤某些区域的肿瘤血流量和氧合显着增加。我们的主要重点是确定这种情况发生的地点、原因以及它如何影响患者对其他应用疗法的反应。

项目成果

Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery.

• DOI: 10.1016/j.ijrobp.2015.05.016
• 发表时间: 2015-09-01
• 期刊: International journal of radiation oncology, biology, physics
• 作者: Song CW;Lee YJ;Griffin RJ;Park I;Koonce NA;Hui S;Kim MS;Dusenbery KE;Sperduto PW;Cho LC
• 通讯作者: Cho LC

Commentary on classic paper in hyperthermic oncology 'Tumour oxygenation is increased by hyperthermia at mild temperatures' by CW Song et al., 1996.

CW Song 等人，1996 年对热肿瘤学经典论文“温和温度下的热疗增加肿瘤氧合”的评论。

• DOI: 10.1080/02656730902758700
• 发表时间: 2009
• 期刊: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
• 作者: Griffin,RobertJ;Corry,PeterM
• 通讯作者: Corry,PeterM

Killing of hypoxic cells by lowering the intracellular pH in combination with hyperthermia.

通过降低细胞内 pH 值并结合热疗来杀死缺氧细胞。

• 发表时间: 1995
• 期刊: Radiation research
• 影响因子: 3.4
• 作者: Lyons,JC;Song,CW
• 通讯作者: Song,CW

Thermal sensitivity and kinetics of thermotolerance in bovine aortic endothelial cells in culture.

培养物中牛主动脉内皮细胞的热敏感性和耐热性动力学。

• DOI: 10.3109/02656739109004981
• 发表时间: 1991
• 期刊: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
• 作者: Sahu,SK;Song,CW
• 通讯作者: Song,CW

Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models.

• DOI: 10.1016/j.ijrobp.2015.07.2275
• 发表时间: 2015-11-01
• 期刊: International journal of radiation oncology, biology, physics
• 作者: Koonce NA;Quick CM;Hardee ME;Jamshidi-Parsian A;Dent JA;Paciotti GF;Nedosekin D;Dings RP;Griffin RJ
• 通讯作者: Griffin RJ