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.

最近的临床试验已经明确表明，热疗显着提高各种恶性肿瘤的治疗反应时，与放疗或化疗联合使用。我们研究的总体目标是通过利用肿瘤和正常组织之间生理特征的差异来找到提高热疗疗效的方法。我们最近发现，抗白血病药物三氧化二砷（ATO）在实验性肿瘤中引起显著的血管关闭。我们的初步研究表明，ATO引起的血管关闭显著改善了肿瘤对愈合的反应。我们将进一步研究ATO引起血管关闭和增强肿瘤中的热损伤的能力（具体目标1）。我们还将阐明ATO引起的血管关闭的机制。特别是，我们将研究各种粘附分子和细胞因子的表达在体外和体内的内皮细胞和肿瘤细胞的变化（具体目标2）。细胞内pH值（pHi）的降低增强了高温的杀细胞作用。我们建议研究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造成的损伤的能力（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的细胞凋亡中的作用，以及该途径如何受到环境pH的影响（具体目标4）。本研究所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和增强肿瘤的热敏性。