MOLECULAR MECHANISMS OF ARA-C THERAPY IN MAN

ARA-C 治疗人类的分子机制

• 批准号: 3168717
• 负责人: DONALD W. KUFE
• 金额: $ 17.85万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-01-01 至 1991-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3168717
• 关键词: DNA directed DNA polymerase; DNA repair; DNA replication; antimetabolites; antineoplastics; cell differentiation; cell membrane; clone cells; combination chemotherapy; conformation; cytosine arabinoside; cytosine nucleotides; cytotoxicity; deoxycytidine; drug metabolism; high performance liquid chromatography; human subject; human therapy evaluation; membrane permeability; membrane structure; myelogenous leukemia; myeloid stem cell; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nucleic acid sequence; nucleoside phosphate kinase; pharmacokinetics; protooncogene; radiotracer; thymidine; tissue /cell culture; tritium; uridine monophosphate

Ara-C is one of the most effective agents in the treatment of acute myelogenous leukemia. The mechanism(s) of action of ara-C and the basis for selectivity against leukemic cells, however, remains unclear. We have previously studied the effects of ara-C incorporation into leukemic cell DNA. The incorporated ara-C residue acts as a relative chain terminator and the extent of incorporation correlates with inhibition of DNA synthesis. Cytostatic concentrations of ara-C induce human leukemic cell differentiation in vitro and alter specific gene expression. Lethal effects at higher ara-C concentration are associated with termination of DNA chain elongation. The work will extend these findings by studying the mechanism(s) responsible for ara-C induced globin gene expression in human K562 erythroleukemia cells. We will extend preliminary studies demonstrating that ara-C alters proto-oncogene expression in human leukemic cells. These effects on specific gene expression will be further studied by monitoring ara-C induced changes in chromatin structure. The effects of ara-C on gene amplification, rereplication of previously replicated DNA segments and chromosomal aberrations will also be studied as events related to the accumulation of DNA replication intermediates. Finally, we will study the in vivo metabolism of ara-C during high dose continuous infusion therapy. The specific aims are: 1) To study the molecular mechanisms of ara-C induced K562 cell differentiation by monitoring specific globin gene expression, DNA methylation and nuclease hypersensitive sites; 2) To monitor the effects of ara-C on proto-oncogene expression in human leukemic cell lines; 3) To study the effects of ara-C on DNA chain elongation, histone expression and chromatin structure; 4) To study the effects of ara-C on gene amplification, endoreduplication and chromosomal aberrations; 5) To study the pharmacodynamics of ara-C in a Phase II trial of high dose continuous infusion therapy for myeloid leukemia.

阿糖胞苷是治疗急性胰腺炎最有效的药物之一， 骨髓性白血病 阿糖胞苷的作用机制及其基础 然而，对白血病细胞的选择性仍然不清楚。 我们有 先前研究了阿糖胞苷掺入白血病细胞的作用， DNA. 掺入的ara-C残基作为相对链终止剂 并且掺入的程度与DNA的抑制相关 合成. 阿糖胞苷对人白血病细胞的抑制作用 体外分化和改变特定基因表达。 致命 在较高的阿糖胞苷浓度的影响与终止 DNA链延长。 这项工作将通过研究机制来扩展这些发现 在人K562中负责ara-C诱导的珠蛋白基因表达 红白血病细胞 我们将扩大初步研究， 阿糖胞苷改变了人类白血病细胞中原癌基因的表达。 这些 将通过监测进一步研究对特定基因表达的影响， ara-C诱导染色质结构的变化。 阿糖胞苷对基因表达的影响 扩增，先前复制的DNA片段的再复制， 染色体畸变也将作为与 DNA复制中间体的积累。 最后，我们将研究 大剂量连续输注治疗期间阿糖胞苷体内代谢。 具体目的是：1）研究阿糖胞苷的分子作用机制 特异性珠蛋白基因调控诱导K562细胞分化 表达、DNA甲基化和核酸酶超敏位点; 2） 阿糖胞苷对白血病原癌基因表达的影响 3）研究阿糖胞苷对DNA链延长的影响， 组蛋白表达和染色质结构; 4）研究 ara-C对基因扩增、核内复制和染色体畸变的影响; 5)研究阿糖胞苷大剂量Ⅱ期临床试验的药效学 持续输注治疗髓系白血病。