TARGETING CELLULAR ONCOGENES WITH DNA-REACTIVE DRUGS

用 DNA 反应药物靶向细胞癌基因

基本信息

批准号：
6173060
负责人：
JAN M WOYNAROWSKI
金额：
$ 10.08万
依托单位：
CANCER THERAPY AND RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-07-01 至 2002-06-30
项目状态：
已结题

项目摘要

DESCRIPTION: The overall objective of this application is to explore the possibility that AT-specific DNA-reactive drugs could preferentially target nuclear matrix-bound oncogene domains. AT-rich domains that are associated with the nuclear matrix play a crucial role in the organization and regulation of DNA replication. Organization of such domains on the nuclear matrix is different both in tumor vs. normal cells and active vs inactive genes. The applicant has shown that several anti tumor, AT-specific, DNA-reactive drugs can bind matrix-associated replication regions, including domains of activated c-myc. Tumor-specific organization of c-myc replication on the nuclear matrix could be a basis for selective drug action in tumor cells. He proposes to test the hypothesis that targeting replication-related regions of activated c-myc offers a potential for enhanced therapeutic benefits. Using the quantitative PCR-stop assay, he will determine the ability of the anti tumor drug bizelesin and other AT-specific, DNA-reactive drugs to preferentially affect the replication domains, matrix associated region (MAR) and origin of replication (ORI) of the c-myc gene. Also, he will verify whether the differences in the c-myc association with the nuclear matrix between tumor and normal cells affect drug ability to damage c-myc sequences. Finally, he will test the idea that abrogation of DNA replication by drug-induced lesions in c-myc MAR and ORI sites can lead to cell death. Understanding drug effects on c-myc oncogene replication domains will provide leads for the design of new therapeutic strategies. The following specific aims are proposed: 1. Determine bizelesin's ability to modify the replication domains of the c-myc oncogene. 2. Determine how association with the nuclear matrix affects the susceptibility of c-myc replication domains to bizelesin. 3. Compare bizelesin's effects on the replication of c-myc MAR sequences in tumor cells vs normal cells.

描述：本应用程序的总体目的是探索 AT特异性DNA反应性药物可能优先靶向的可能性核基质结合的癌基因域。相关的富裕域随着核矩阵在组织中起着至关重要的作用调节DNA复制。在核上组织此类领域基质在肿瘤和正常细胞和活性与非活性的矩阵都不同基因。申请人表明，几种抗肿瘤特异性的 DNA反应性药物可以结合基质相关的复制区，包括激活C-Myc的域。 C-MYC的肿瘤特异性组织对核基质的复制可能是选择性药物作用的基础在肿瘤细胞中。他建议检验靶向的假设激活C-MYC的复制相关区域为增强的治疗益处。使用定量PCR-Stop测定法，他将确定抗肿瘤药物双齐氏素和其他抗肿瘤药物的能力以特异性的DNA反应性药物优先影响复制域，矩阵相关区域（MAR）和复制的起源（ORI）的起源 C-MYC基因。此外，他将验证C-MYC的差异是否存在与肿瘤和正常细胞之间的核基质相关损害C-MYC序列的药物能力。最后，他将测试通过药物诱导的C-MYC MAR和ORI中的药物诱导的病变清除DNA复制站点可以导致细胞死亡。了解药物对c-myc癌基因的影响复制域将为设计新治疗的设计提供线索策略。提出了以下具体目标：1。确定 Bizelesin修改C-Myc癌基因的复制域的能力。 2。确定与核基质的关联如何影响 C-MYC复制域对Bizelesin的敏感性。 3。比较 Bizelesin对肿瘤细胞中C-Myc MAR序列复制的影响与正常细胞。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Region-specific DNA damage by AT-specific DNA-reactive drugs is predicted by drug binding specificity.

AT 特异性 DNA 反应药物造成的区域特异性 DNA 损伤可以通过药物结合特异性来预测。

DOI：
10.1021/bi000729k
发表时间：
2000
期刊：
Biochemistry
影响因子：
2.9
作者：
Woynarowski,JM;Napier,C;Trevino,AV;Arnett,B
通讯作者：
Arnett,B

Enhanced topoisomerase II targeting by annamycin and related 4-demethoxy anthracycline analogues.

安霉素和相关的 4-去甲氧基蒽环类类似物增强拓扑异构酶 II 靶向性。

DOI：
发表时间：
2004
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Trevino,AlexV;Woynarowska,BarbaraA;Herman,TerenceS;Priebe,Waldemar;Woynarowski,JanM
通讯作者：
Woynarowski,JanM

The genome factor in region-specific DNA damage: the DNA-reactive drug U-78779 prefers mixed A/T-G/C sequences at the nucleotide level but is region-specific for long pure AT islands at the genomic level.

区域特异性 DNA 损伤中的基因组因素：DNA 反应药物 U-78779 在核苷酸水平上更喜欢混合 A/T-G/C 序列，但在基因组水平上对长纯 AT 岛具有区域特异性。

DOI：
10.1021/bi011907s
发表时间：
2002
期刊：
Biochemistry
影响因子：
2.9
作者：
Herzig,MaryanneCS;Rodriguez,KarlA;Trevino,AlexV;Dziegielewski,Jaroslaw;Arnett,Brenda;Hurley,Laurence;Woynarowski,JanM
通讯作者：
Woynarowski,JanM

AT islands - their nature and potential for anticancer strategies.

AT 岛屿 - 其性质和抗癌策略的潜力。