Physiological Factors in Hyperthermia

最近的临床试验明确地证明，当热疗与放疗或化疗联合使用时，显著改善了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的差异来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)在实验性肿瘤中会导致显著的血管关闭。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导致血管关闭和增强肿瘤热损伤的能力(特定目标1)。我们还将阐明ATO导致血管关闭的潜在机制。特别是，我们将研究血管内皮细胞和肿瘤细胞在体外和体内表达各种黏附分子和细胞因子的变化(特定目标2)。细胞内pH(Phi)的降低加强了高温对细胞的杀灭作用。我们建议研究新型PHI调控机制的抑制剂SO427和S3705固化细胞内环境和增加热疗对肿瘤的损害的能力(特定目标3)。热诱导细胞凋亡的机制，尤其是低pH环境引起的热敏化机制尚不清楚。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(特定目标4)。本研究中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，显著改善肿瘤的温度，增强肿瘤的热敏性。

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.