RADIATION SENSITIZERS: INTERACTIONS

辐射增敏剂咪唑(MISO)可选择性地增强 某些常规化疗药物的体外和体外疗效 在活体内。在几乎每个被测试的系统中，肿瘤的增强 毒性已经超过了正常组织损伤的任何实质性增加。 为了准确评估这种疗法的潜力，并 最大限度地利用它，有必要建立潜在的 机械装置。这项提案的一个长期目标是研究 细胞与MISO孵育后的化学增强机制 用亚硝脲治疗。DNA交联的程度和动力学 治疗后的形成将在EMT-6细胞和两名人类 细胞系IMR-90和VA-13。后一种细胞系缺乏(Mer-) 烷基转移酶活性和氯乙基切除效率低 亚硝脲处理后DNA的单加合物，而前者 展示这一能力(Mer+)。烷基转移酶活性在细胞周期调控中的作用 将检查MISO的化学增强作用。谷胱甘肽(GSH)衰竭 也将受到监控。这两种影响都将与 化学增强和后孵化时的化学增强丧失 亚硝脲治疗后，MISO出现延迟。 拟议研究的第二个长期目标是综合 基于我们以前的构效关系改进的化学增强剂 调查。具体地说，实验将被设计来测试 假设侧链的增加，能够产生一个 异氰酸酯，到一个含氮杂环可以提高化学增强作用 活动。在初步实验中，这种方法被证明是非常 很有希望。综合努力将尝试定义特定的结构 影响化学增敏、放射增敏和 异氰酸酯类硝基杂环化合物的体外细胞毒性研究 在活体内。

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.