Physiological Factors in Hyperthermia

热疗的生理因素

• 批准号: 6708072
• 负责人: Chang Won Song
• 金额: $ 30.61万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6708072
• 关键词: acidity /alkalinity; apoptosis; arsenic; blood flow measurement; ceramides; combination cancer therapy; laboratory mouse; laboratory rat; neoplasm /cancer blood supply; neoplasm /cancer thermotherapy; neoplastic cell; oxides; tissue /cell culture

Recent clinical trials have unequivocally demonstrated that hyperthermia significantly improves the treatment response of various malignancies when used in combination with radiotherapy or chemotherapy. The overall objective of our study is to find means to improve the efficacy of hyperthermic treatment by exploiting differences in the physiological characteristics between tumors and normal tissues. We recently discovered that the anti-leukemia agent arsenic trioxide (ATO) causes a dramatic vascular shutdown in experimental tumors. Our pilot studies demonstrated that the vascular shutdown caused by ATO markedly improves the tumor response to healing. We will further investigate the ability of ATO to cause vascular shutdown and enhance hyperthermic damage in tumors (Specific Aim 1). We will also elucidate the mechanisms underlying the vascular shutdown caused by ATO. In particular, we will investigate the changes in expression of various adhesion molecules and cytokines by endothelial cells and tumor cells in vitro and in vivo (Specific Aim 2). A reduction of intracellular pH (pHi) potentiates the cytocidal effect of hyperthermia. W propose to investigate the ability of SO427 and S3705, novel inhibitors of pHi control mechanisms, to solidify the intracellular environment and increase the damage to tumors caused by hyperthermic treatment (Specific Aim 3). The mechanisms of heat-induced apoptosis, in particular, the mechanisms of thermosensitization caused by low pH environment have not yet been clearly defined. We plan to investigate the role of the ceramide signaling in heat-induced apoptosis and how this pathway is influenced by environmental Ph (Specific Aim 4). The information to be obtained in our studies will enable us to design rational treatment regimens in the clinic to markedly improve tumor heating and augment tumor thermosensitivity.

最近的临床试验明确证明，热疗与放疗或化疗联合使用可显着改善各种恶性肿瘤的治疗反应。我们研究的总体目标是通过利用肿瘤和正常组织之间的生理特征差异来寻找提高热疗疗效的方法。我们最近发现抗白血病剂三氧化二砷 (ATO) 会导致实验性肿瘤中的血管急剧关闭。我们的初步研究表明，ATO 引起的血管关闭显着改善了肿瘤对愈合的反应。我们将进一步研究 ATO 导致血管关闭和增强肿瘤热损伤的能力（具体目标 1）。我们还将阐明 ATO 引起血管关闭的机制。特别是，我们将在体外和体内研究内皮细胞和肿瘤细胞表达的各种粘附分子和细胞因子的变化（具体目标2）。细胞内 pH (pHi) 的降低可增强热疗的杀细胞作用。 W 提议研究 SO427 和 S3705（pHi 控制机制的新型抑制剂）固化细胞内环境并增加热疗对肿瘤损伤的能力（具体目标 3）。热诱导细胞凋亡的机制，特别是低pH环境引起的热敏化机制尚未明确。我们计划研究神经酰胺信号传导在热诱导细胞凋亡中的作用以及该途径如何受到环境 Ph 值的影响（具体目标 4）。我们研究中获得的信息将使我们能够在临床上设计合理的治疗方案，以显着改善肿瘤加热并增强肿瘤热敏感性。