SYSTEMIC HYPERTHERMIA AND MISONIDAZOLE CHEMOPOTENTIATION

辐射增敏剂米索(MISO)可以选择性地 增强某些常规药物的有效性 体外和体内的化疗药物。在预赛中 我们的实验证明了这种化学增强作用 温和的调味汁可以显著增强味佐的效果 缺氧时体温过高(41摄氏度，1小时)，但不是 有氧条件下，表明高温的添加 对药物敏感剂的组合可能会导致显著的 治疗优势。拟议方案的总体目标 研究内容有1)在活体比较中评价这一假说 肿瘤反应增强(KHT肉瘤)和正常组织 味精联合用药对人体的损害 结合全身热疗，2)确定参数 影响三个变量间相互作用的体外实验研究 受控实验环境和3)确定 氧的相互作用机理及影响(S) 把注意力集中在他们的表情上。实验表明， 热疗，与其对化疗的影响无关 药剂，增加一剂的化学增强效率 MISO，可能是通过增加硝基还原酶(NR)活性，以及 氧敏感反应。这种增强的化学潜力 效率可能被证明在临床上具有重要意义，因为 患者的化学增强可能受到以下因素的限制 提供足够剂量的味增。 拟议的研究将广泛使用统计数据- 有动机的实验设计以确定 温度、氧气浓度、敏化剂剂量和 利用细胞存活率对化学增强表达进行测序， 以肿瘤生长延迟和硝酸还原酶活性为终点。 其他实验将利用多细胞肿瘤球体 模型和选择性胰酶消化技术以确定 治疗对接触有氧和低氧人群的影响 同时并确定热增强是否 在味精浓度和药代动力学条件下是可能的 在临床上是可以实现的。这些后来的实验将利用 一种设计成允许药代动力学的椭圆形治疗装置 在体外进行建模。最后，高温对空气质量的影响 耐亚硝脲的化学增强，化学增强- 耐药的Mer+肿瘤细胞(约80%的人类肿瘤表达 Mer+表型)也将作为初步评估 实验表明，外加热量可以克服这种现象。 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.