SYSTEMIC HYPERTHERMIA AND MISONIDAZOLE CHEMOPOTENTIATION

放射增敏剂米索唑（MISO）可以选择性地 加强某些常规措施的有效性， 体外和体内的化疗剂。 初步 我们的实验已经证明，这种化学增强 MISO的效果可以通过轻度的 缺氧条件下的高温（41 ℃，1小时），但不 有氧条件下，这表明高温的加入 药物-致敏剂组合可能会导致显著的 治疗优势 建议的总体目标 研究是1）在体内评估这一假设， 增强肿瘤反应（KHT肉瘤）和正常组织 当MISO-药物组合给药时， 结合全身热疗，2）定义参数 影响体外三个变量之间的相互作用， 控制实验环境和3）确定 相互作用的机制和氧的影响 专注于他们的表情。 实验表明 热疗，与其对化疗药物的影响无关 在某些实施方案中，本发明提供了一种化学增强剂，其增加了一剂化学增强剂的化学增强效率。 MISO，可能通过增加硝基还原酶（NR）活性， 氧敏反应 这种增强的化学增强作用 随着成功，效率可能会被证明具有临床意义 患者的化学增强作用可能受到不能 提供足够的MISO剂量。 这项研究将广泛使用统计数据- 有动机的实验设计，以确定 温度、氧浓度、敏化剂剂量，以及 使用细胞存活对化学增强的表达进行测序， 肿瘤生长延迟和硝基还原酶活性作为终点。 其他实验将利用多细胞肿瘤球体 模型和选择性胰蛋白酶消化技术，以确定 处理对暴露于需氧和缺氧人群的影响 同时确定热增强是否 在MISO浓度和药物动力学下可能存在 在临床上可以实现。 这些后期实验将利用 设计成允许药代动力学的球体治疗装置 体外建模。 最后，热量对 抗亚硝基脲的化学增强作用，化学增强作用- 耐药Mer+肿瘤细胞（约80%的人类肿瘤表达Mer+， Mer+表型）也将作为初步评估 实验表明，加热可以克服 这种表型的抗性。

The radiation sensitizer Misonidzaole (MISO) can selectively potentiate the effectiveness of certain conventional chemotherapeutic agents in vitro and in vivo. In preliminary experiments we have demonstrated that this chemopotentiating effect of MISO can be significantly augmented by mild hyperthermia (41 degrees C, 1 hr) under oxygen-deficient, but not aerobic conditions, suggesting that the addition of hyperthermia to drug-sensitizer combinations might result in a significant therapeutic advantage. The overall objectives of the proposed research are 1) to evaluate this hypothesis in vivo comparing enhancement of tumor response (KHT sarcoma) and normal tissues damage when MISO-drug combinations are administered in conjunction with whole-body hyperthermia, 2) define parameters influencing the interactions among the three variables in vitro in controlled experimental environments and 3) determine the mechanism(s) of the interactions and the influence of oxygen concentration on their expression. Experiments indicate that hyperthermia, independent of its effect on the chemotherapeutic agent, increases the chemopotentiating efficiency of a dose of MISO, possibly by increasing nitroreductase (NR) activity, an oxygen sensitive reaction. This enhanced chemopotentiating efficiency might prove clinically significant as the success of chemopotentiation in patients may be limited by an inability to deliver adequate MISO doses. The proposed research will make extensive use of statistically- motivated experimental designs to determine the significance of temperature, oxygen-concentration, sensitizer dose, and sequencing on expression of chemopotentiation using cell survival, tumor-growth delay and nitroreductase activity as endpoints. Other experiments will utilize the multi-cell tumor spheroid model and selective trypsinization techniques to determine the effect of treatment on aerobic and hypoxic populations exposed simultaneously and to determine whether thermal enhancements are possible at MISO concentrations and pharmaco-kinetics achievable in the clinic. These later experiments will make use of a spheroid treatment device designed to permit pharmacokinetic modeling in vitro. Finally, the effect of heat on the chemopotentiation of nitrosourea-resistant, chemopotentiation- resistant Mer+ tumor cells (about 80% of human tumors express the Mer+ phenotype) will also be evaluated as preliminary experiments indicate that the addition of heat can overcome the resistance of this phenotype.