CHRONIC MYELOGENOUS LEUKEMIA--THERAPEUTIC APPROACH

慢性粒细胞白血病——治疗方法

• 批准号: 3197784
• 负责人: NEIL W GIBSON
• 金额: $ 15.51万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-02-01 至 1993-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3197784
• 关键词: DNA; DNA repair; alkylating agents; alkylation; antileukemic agent; busulfan; chronic myelogenous leukemia; combination chemotherapy; detoxification; drug metabolism; drug resistance; gel electrophoresis; genetic transcription; high performance liquid chromatography; human tissue; mass spectrometry; molecular pathology; neoplasm /cancer pharmacology; nucleic acid sequence; tissue /cell culture

Chronic myelogenous leukemia (CML) is a malignancy which can be successfully controlled by chemotherapy for a number of years. Ultimately, however, all patients develop resistance to drug therapy and their prognosis markedly deteriorates. There is, therefore, an urgent need for the development of new compounds with an improved therapeutic index, information which can explain the mechanisms involved in the development of drug resistance, and the development of alternative drug combinations which can overcome the resistant phase of this disease. This proposal deals directly with these three issues. 1,7-heptanediol disulfamate (Hepsulfam NSC-329680) is an active antileukemic agent that has recently been entered into phase 1 clinical trials by the National Cancer Institute. The mechanism of action of this compound is unknown, therefore, one aim of this proposal is to identify the mechanism by which hepsulfam elicits its antileukemic mechanism. This will be achieved by directly comparing the ability of hepsulfam to induce DNA damage, in human leukemia cell lines, with that of busulfan (a currently used drug of choice in CML) 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 analyzed by high pressure liquid chromatography and identified by mass spectroscopy. DNA sequence specificity of this agent will be analyzed by both Maxam and Gilbert and Sangers dideoxy sequencing methods. A human leukemic cell line, with acquired resistance to either busulfan or hepsulfam, will be established. This will allow a careful analysis of the cross-resistance patterns that might be expected to occur clinically. In addition, the importance of detoxification or DNA repair, as mechanisms of drug resistance in CML, will be assessed. Finally, this information will be used in order to develop more effective therapeutic combinations with which to treat CML.

慢性粒细胞性白血病（CML）是一种恶性肿瘤 通过化学疗法成功控制了多年。 然而，最终，所有患者都对药物治疗和 它们的预后显着恶化。 因此，有一个紧急的 需要开发新化合物，并有改进的治疗方法 索引，可以解释涉及机制的信息 耐药性的发展和替代药物的发展 可以克服该疾病的抗性阶段的组合。 这 提案直接处理这三个问题。 1,7-甲烷二醇二硫酸盐（HEPULFAM NSC-329680）是活跃的 最近已进入1阶段临床的抗白血病药物 国家癌症研究所的试验。 行动的机制 因此，化合物未知，因此该提案的目的是确定 甲硫酸引起其抗白血病机制的机制。 这 将直接比较赫普硫素诱导的能力来实现 DNA损伤，在人类白血病细胞系中，与busulfan的损伤（a 目前在CML中使用的药物）通过碱性技术 洗脱。 对分子水平的这些病变的更详细分析 将执行。 DNA碱加合物将通过高压分析 液相色谱法，并通过质谱鉴定。 DNA序列 Maxam和Gilbert以及 Sangers Dideoxy测序方法。 人类白血病细胞系，带有 将建立对Busulfan或Hepsulfam的获得的抵抗。 这将允许仔细分析交叉抗性模式 可能会在临床上发生。 另外，重要性 排毒或DNA修复，作为CML耐药性的机制， 将被评估。 最后，将使用此信息来 开发更有效的治疗组合来治疗CML。