MOLECULAR MECHANISMS OF ARA-C THERAPY IN MAN
ARA-C 治疗人类的分子机制
基本信息
- 批准号:3168716
- 负责人:
- 金额:$ 19.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:DNA directed DNA polymerase DNA repair antimetabolites antineoplastics cell differentiation cell membrane clone cells combination chemotherapy conformation cytosine arabinoside 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
项目摘要
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白血病最有效的药物之一。
骨髓性白血病。阿糖胞苷的作用机制(S)及其基础
然而,对白血病细胞的选择性仍不清楚。我们有
先前研究了Ara-C掺入白血病细胞的作用
DNA掺入的Ara-C残基充当相对的链终止剂
而掺入的程度与DNA的抑制有关
综合。细胞抑制浓度阿糖胞苷诱导人白血病细胞
在体外分化和改变特定基因的表达。致死
较高的Ara-C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(S)
Ara-C诱导人K562细胞珠蛋白基因表达的机制
红白血病细胞。我们将扩大初步研究,论证
阿糖胞苷改变人白血病细胞原癌基因的表达。这些
对特定基因表达的影响将通过监测进一步研究
Ara-C引起染色质结构的改变。阿糖胞苷对基因的影响
先前复制的DNA片段的扩增、重新复制和
染色体异常也将作为与
DNA复制中间体的积累。最后,我们将研究
大剂量持续输注治疗过程中阿糖胞苷在体内的代谢
具体目的是:1)研究Ara-C的分子机制
监测特异性珠蛋白基因诱导K562细胞分化
表达、DNA甲基化和核酸酶敏感部位;2)
监测阿糖胞苷对人白血病原癌基因表达的影响
3)研究Ara-C对DNA链延长的影响。
组蛋白表达与染色质结构的关系;4)研究组蛋白表达与染色质结构的关系
Ara-C对基因扩增、内复制和染色体畸变的影响;
5)大剂量二期试验研究阿糖胞苷的药效学
髓系白血病的持续输注治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DONALD W. KUFE其他文献
DONALD W. KUFE的其他文献
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{{ truncateString('DONALD W. KUFE', 18)}}的其他基金
Targeting MUC1-C with an antibody drug conjugate for the therapy of advanced prostate cancer
使用抗体药物偶联物靶向 MUC1-C 治疗晚期前列腺癌
- 批准号:
10512804 - 财政年份:2022
- 资助金额:
$ 19.36万 - 项目类别:
Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression
靶向 MUC1-C 治疗小细胞肺癌进展
- 批准号:
10354347 - 财政年份:2022
- 资助金额:
$ 19.36万 - 项目类别:
Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression
靶向 MUC1-C 治疗小细胞肺癌进展
- 批准号:
10563188 - 财政年份:2022
- 资助金额:
$ 19.36万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
10004595 - 财政年份:2018
- 资助金额:
$ 19.36万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
9789217 - 财政年份:2018
- 资助金额:
$ 19.36万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
10478059 - 财政年份:2018
- 资助金额:
$ 19.36万 - 项目类别:
MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
MUC1-C 是逆转免疫逃避和免疫疗法耐药性的靶点
- 批准号:
10224740 - 财政年份:2018
- 资助金额:
$ 19.36万 - 项目类别:
MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer
MUC1-C 癌蛋白在非小细胞肺癌中逃避免疫破坏
- 批准号:
9913473 - 财政年份:2012
- 资助金额:
$ 19.36万 - 项目类别:
MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer
MUC1-C 癌蛋白在非小细胞肺癌中逃避免疫破坏
- 批准号:
9238148 - 财政年份:2012
- 资助金额:
$ 19.36万 - 项目类别:
Functional role of the MUC1-C oncoprotein in non-small cell lung cancer
MUC1-C 癌蛋白在非小细胞肺癌中的功能作用
- 批准号:
8837576 - 财政年份:2012
- 资助金额:
$ 19.36万 - 项目类别:
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