Physiological Factors in Hyperthermia

最近的临床试验明确表明，当与放疗或化疗联合使用时，热疗显著改善了各种恶性肿瘤的治疗反应。我们研究的总体目的是利用肿瘤与正常组织生理特性的差异，寻找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剧烈的血管关闭。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在肿瘤中引起血管关闭和增强热损伤的能力（Specific Aim 1）。我们还将阐明ATO引起的血管关闭的机制。特别是，我们将在体外和体内研究内皮细胞和肿瘤细胞对各种粘附分子和细胞因子的表达变化（Specific Aim 2）。细胞内pH值（pHi）的降低增强了热疗的细胞杀伤作用。我们拟研究pHi控制机制的新型抑制剂SO427和S3705固化细胞内环境和增加高温治疗对肿瘤损伤的能力（Specific Aim 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在热诱导细胞凋亡中的作用，以及这一途径如何受到环境Ph的影响（Specific Aim 4）。我们在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，显著改善肿瘤加热，增强肿瘤热敏性。

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.