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MECHANISM OF CYTOTOXICITY OF DEOXYADENOSINE AND ANALOGS

脱氧腺苷及其类似物的细胞毒性机制

基本信息

批准号：
3178066
负责人：
RAYMOND L BLAKLEY
金额：
$ 12.33万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-02-01 至 1989-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3178066
关键词：
DNA directed DNA polymerase adenosine triphosphate bromine chlorine cytotoxicity deoxyadenosines enzyme inhibitors laboratory mouse lymphoblast oxidoreductase purine nucleosides ribonucleotides thymus tissue /cell culture

项目摘要

The biochemical mechanisms by which deoxyadenosine (in the prsence of an adenosine deaminase inhibitor), 2-chlorodeoxyadenosine and 2-bromodeoxyadenosine exert their cytotoxic effects on cells will be further investigated and compared. These nucleosides are markedly cytotoxic to human T-lymphoblastoid, B-lymphoblastoid and myeloid cell lines in cutlure and produc therapeutic responses against murine tumors and against human hemaologic malignancies. One part of the project will be aimed at determining whether inhibition of ribonucleoside diphosphate reductase by tripyhospahtes of the nucleosides is the main mechanism of cytotoxicity. Some of these experiments will involved work with intact cells, and for this purpose the human T-lymphoblastoid cell line CCRF-CEM will be used. Other studies will employ partially purified reductase from L1210 cells and highly purified reductase from calf thymus. In the second part of the project evidence will be obtained as to whether inhibition of DNA synthesis by these necleosides involves another signifiicant mechanism. Particular attention will be given to the possibility that DNA polymerase Alpha is inhibited, or that incorporation of analogue into DNA inhibits chain elongation. Purified DNA polymerase Alpha will be used for these experiments. The use of cells selected for resistance to the analogues will also be used in both parts of the project.

脱氧腺苷(An)的生物化学机制腺苷脱氨酶抑制剂)、2-氯脱氧腺苷和 2-溴脱氧腺苷对细胞的细胞毒作用将被进一步调查和比较。这些核苷明显对人T淋巴母细胞、B淋巴母细胞和髓系细胞的细胞毒作用培养和生产对小鼠肿瘤的治疗反应和对抗人类血液系统恶性肿瘤的药物。该项目的一个部分将旨在确定抑制核苷三联体核糖核苷二磷酸还原酶是细胞毒性的主要机制。其中一些实验将涉及与完整细胞的工作，为此，人类将使用T淋巴母细胞系CCRF-CEM。其他研究将使用L1210细胞的部分纯化的还原酶和高纯度的小牛胸腺中的还原酶。在项目的第二部分，将获得证据，以确定是否这些核苷对DNA合成的抑制涉及到另一个方面意义重大的机制。我们会特别注意 DNA聚合酶α被抑制的可能性，或者掺入类似物进入DNA会抑制链的延长。纯化的DNA聚合酶阿尔法将被用于这些实验。也将使用对类似物具有抵抗力的电池在项目的两个部分。