MECHANISM OF ACTION OF SULFONATE ESTER ANTICANCER DRUGS

磺酸酯类抗癌药物的作用机制

• 批准号: 3459034
• 负责人: NEIL W GIBSON
• 金额: $ 8.38万
• 依托单位: AMC CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1993-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3459034
• 关键词: DNA; DNA repair; alkylating agents; antineoplastics; cell bank /registry; chemical structure function; drug adverse effect; drug metabolism; drug resistance; gel electrophoresis; high performance liquid chromatography; macromolecule; neoplasm /cancer pharmacology; sulfonate

1,5,2,4-dioxadithiepane-2,2,4,4-tetraoxide (cyclidisone, NSC- 348948) is an active antitumor agent that is being considered for phase I clinical trials in humans and is currently under toxicological evaluation. The mechanism of action of this compound is unknown, therefore, the major aim of this proposal is to identify the mechanism by which cyclidisone elicits its antitumor activity. The chemistry of cyclidisone suggests that it is an alkylating agent with bifunctional capabilities. This proposal will thus concentrate on the ability of cyclidisone to react with DNA and/or nuclear proteins. Specific interests include the identification of the nuclear reactions of cyclidisone in order to pinpoint which particular lesions may be responsible for its selective toxicity against human tumor cells. This will be achieved by a comparison of the macromolecular DNA damage induced by cyclidisone in a sensitive (BE) and resistant (HT-29) human colon carcinoma cell lines by the technique of alkaline elution. A more detailed analysis of these lesions at the molecular level will be performed. DNA base adducts will be analysed by high pressure liquid chromatography and DNA-protein crosslinks will be identified by cesium chloride gradients and gel electorphoresis. A human cell line with acquired resistance to cyclidisone will be established. The importance of DNA repair as a mechanism of drug resistance will be assessed. The effect that structural modifications of the parent compound have upon toxicity and nuclear reactivity will be determined. The elucidation of the mechanism by which cyclidisone selectively kills human tumor cells is very important to the future development of this new class of anticancer agent.

1,5,2,4-Dioxadithiepane-2,2,4,4-四氧化物（Cyclidisone，NSC-- 348948）是一种正在考虑的活性抗肿瘤剂 I期临床试验在人类中，目前正在 毒理学评估。 行动的机制 因此，化合物尚不清楚，因此该提议的主要目的是 确定儿基酮引起的机制 抗肿瘤活性。 环丙酮的化学表明它 是具有双功能能力的烷基化剂。 这个建议 因此，将集中于环丙酮与反应的能力 DNA和/或核蛋白。 具体利益包括 鉴定儿基核苷的核反应是为了 查明哪些特定病变可能负责 对人肿瘤细胞的选择性毒性。 这将是 通过比较大分子DNA损伤来实现 通过敏感（BE）和抗性（HT-29）诱导的cyclidisone诱导 人类结肠癌细胞系通过碱性技术 洗脱。 对这些病变的更详细分析 将进行分子水平。 DNA碱加合物将是 通过高压液相色谱和DNA蛋白分析 交叉链接将通过氯化葡萄酸盐和凝胶鉴定 选举。 具有获得抗性的人类细胞系 将建立cyclidisone。 DNA修复的重要性 将评估耐药性机制。 效果 母体化合物的结构修饰 将确定毒性和核反应性。 这 阐明儿基酮有选择性的机制 杀死人肿瘤细胞对未来非常重要 开发这种新的抗癌剂。