DETECTION AND CURING OF AMPLIFIED GENES IN HUMAN CANCER
人类癌症扩增基因的检测和治愈
基本信息
- 批准号:3549172
- 负责人:
- 金额:$ 39.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1988
- 资助国家:美国
- 起止时间:1988-08-01 至 1995-07-31
- 项目状态:已结题
- 来源:
- 关键词:DNA binding protein DNA replication DNA replication origin DNA topoisomerases NAD nucleosidase alcohol oxidoreductases amides antineoplastics athymic mouse benzimidazole analog camptothecin clone cells cooperative study disease /disorder model drug design /synthesis /production drug resistance drug screening /evaluation enzyme inhibitors etoposide extrachromosomal DNA gel electrophoresis genetic mapping human tissue in situ hybridization model design /development molecular cloning molecular site natural gene amplification neoplasm /cancer genetics neoplastic cell nicotinamide nucleic acid inhibitor nucleic acid sequence protooncogene ribonucleotide reductase site directed mutagenesis tissue /cell culture triazoles
项目摘要
Proto-oncogenes and other genes which may be involved in the development or
progression of human malignancies are often found to be amplified in many
human neoplasms. The overexpression of the gene product in such cases is
believed to contribute to tumorigenicity. In vivo, the amplified genes are
most frequently detected in acentric, autonomously replicating
extrachromosomal molecules. This proposal presents a two pronged approach
for the development of methods to eliminate extrachromosomally amplified
sequences as a means of reducing tumorigenicity. The first approach
extends observations made over the past two years in this Drug Discovery
Group that ribonucleotide reductase and topoisomerase inhibitors can
accelerate the elimination of amplified proto-oncogenes and drug resistance
genes from a variety of cell lines in cell culture to reduce soft agar
cloning efficiency and increase drug sensitivity, respectively.
Experiments are proposed to test new drugs, alone and in combination, to
accelerate the loss rates obtained thus far. An in vivo mouse model will
be developed to assess the generality of the in vitro work, and to provide
a precedent for implementation of the best strategies in human clinical
trials. The molecular mechanisms of elimination will also be investigated
to enable the development of additional theoretically based and potentially
superior strategies. The second approach will involve the design of
molecular reagents which specifically interact with, and inhibit the
function of, the replication origin(s) which drive the replication of the
extrachromosomal elements. This will be accomplished by the molecular
isolation of mammalian replication origins and determination of the minimum
sequence necessary for them to function in vivo. Two strategies are
proposed to determine whether large regions of DNA are necessary to elicit
origin function, or whether small DNA fragments can comprise an origin as
long as they are first "imprinted" by integration into a chromosome. The
minimum functional regions will be sequenced, analyzed for protein binding
sites, and relevant sites mutated in vitro to assess the functional
consequences. This information will be used to design and develop origin-
specific oligonucleotide inhibitors, and the functional assays will then be
used to assess their effectiveness in vitro and in vivo. Together, the two
approaches offer a balance between general and highly site specific new
strategies for the treatment of human neoplasms in which gene amplification
may augment tumor phenotype.
原癌基因和其他可能参与肿瘤发展的基因
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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Geoffrey Myles Wahl其他文献
Geoffrey Myles Wahl的其他文献
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{{ truncateString('Geoffrey Myles Wahl', 18)}}的其他基金
Combining single cell approaches and a developmental perspective to discover stem cell control circuits and the cellular and molecular bases of cancer heterogeneity
结合单细胞方法和发育视角来发现干细胞控制回路以及癌症异质性的细胞和分子基础
- 批准号:
9115083 - 财政年份:2015
- 资助金额:
$ 39.7万 - 项目类别:
Combining single cell approaches and a developmental perspective to discover stem cell control circuits and the cellular and molecular bases of cancer heterogeneity
结合单细胞方法和发育视角来发现干细胞控制回路以及癌症异质性的细胞和分子基础
- 批准号:
8955700 - 财政年份:2015
- 资助金额:
$ 39.7万 - 项目类别:
Combining single cell approaches and a developmental perspective to discover stem cell control circuits and the cellular and molecular bases of cancer heterogeneity
结合单细胞方法和发育视角来发现干细胞控制回路以及癌症异质性的细胞和分子基础
- 批准号:
10219974 - 财政年份:2015
- 资助金额:
$ 39.7万 - 项目类别:
High throughput screen for inhibitors of the mdm2/mdmx interaction
mdm2/mdmx 相互作用抑制剂的高通量筛选
- 批准号:
7844780 - 财政年份:2010
- 资助金额:
$ 39.7万 - 项目类别:
High throughput screen for inhibitors of the mdm2/mdmx interaction
mdm2/mdmx 相互作用抑制剂的高通量筛选
- 批准号:
8018614 - 财政年份:2010
- 资助金额:
$ 39.7万 - 项目类别:
Mouse Models to Elucidate p53 Regulatory Mechanisms
阐明 p53 调节机制的小鼠模型
- 批准号:
6881681 - 财政年份:2003
- 资助金额:
$ 39.7万 - 项目类别:
Mouse Models to Elucidate p53 Regulatory Mechanisms
阐明 p53 调节机制的小鼠模型
- 批准号:
6736855 - 财政年份:2003
- 资助金额:
$ 39.7万 - 项目类别:
Mouse Models to Elucidate p53 Regulatory Mechanisms
阐明 p53 调节机制的小鼠模型
- 批准号:
7214636 - 财政年份:2003
- 资助金额:
$ 39.7万 - 项目类别:
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