RADIATION SENSITIZERS: INTERACTIONS WITH OTHER MODALITI

放射增敏剂米索咪唑（MISO）可选择性增强放射性核素的放射性， 某些常规化疗剂的体外有效性， in vivo. 在几乎所有的测试系统中，肿瘤的增强 毒性已经超过正常组织损伤的任何伴随增加。 为了准确评估这种疗法的潜力， 为了充分利用它，有必要建立基础 机制等 这项建议的一个长远目标是研究 当细胞与MISO孵育后， 用亚硝基脲治疗。 DNA交联的程度和动力学 将在EMT-6细胞和两个人中评估治疗后的细胞因子形成。 细胞系IMR-90和VA-13。 后一种细胞系缺乏（Mer-） 烷基转移酶活性和在切除氯乙基 亚硝基脲处理后，DNA的单加合物，而前者 证明了这种能力（Mer+）。 烷基转移酶活性在 将检查MISO的化学增强作用。 谷胱甘肽（GSH）耗竭 也将受到监督。这两种影响将与 化学增强和孵育后化学增强的丧失 亚硝基脲治疗后MISO延迟。 拟议研究的第二个长期目标是综合 基于我们先前的结构-活性的改进的化学增强剂 调查事务所 具体而言，实验将被设计为测试 假设添加侧链，能够产生 异氰酸酯，氮杂环可以提高化学增效 活动 在初步实验中，这种方法已经证明非常 很有希望 综合努力将试图定义特定的结构 影响化学增敏、放射增敏和 体外异氰酸酯生成硝基杂环的细胞毒性特性， in vivo.

The radiation sensitizer Misonidazole (MISO) can selectively potentiate the effectiveness of certain conventional chemotherapeutic agents in vitro and in vivo. In virtually every system tested, the enhancement of tumor toxicity has exceeded any concommitant increase in normal tissue damage. In order to accurately evaluate the potential of this therapy and to exploit it to the fullest, it is necessary to establish underlying mechanisms. One long term objective of this proposal is to examine the mechanisms of chemopotentiation when cells are incubated with MISO after treatment with nitrosoureas. The extent and kinetics of DNA cross-link formation after treatment will be assessed in EMT-6 cells and two human cell lines, IMR-90 and VA-13. The latter cell line is deficient (Mer-) in alklytransferase activity and inefficient at excising chloroethyl monoadducts from DNA after nitrosourea treatment, while the former demonstrates this ability (Mer+). The role of alkyltransferase activity in chemopotentiation by MISO will be examined. Glutathione (GSH) depletion will also be monitored. Both effects will be compared to the magnitude of chemopotentiation and the loss of chemopotentiation when post-incubation with MISO is delayed after nitrosourea treatment. The second long term objective of the proposed research is to synthesize improved chemopotentiating agents based on our previous structure-activity investigations. Specifically, experiments will be designed to test the hypothesis that the addition of a side chain, capable of generating an isocyanate, to a nitrogen heterocycle can improve chemopotentiating activity. In preliminary experiments this approach has proven very promising. Synthetic efforts will attempt to define specific structural parameters influencing the chemosensitizing, radiosensitizing, and cytotoxic properties of isocyanate-generating nitroheterocyles in vitro and in vivo.