MISMATCH REPAIR DEFECTS AND HUMAN TUMOR RADIOSENSITIZATI

错配修复缺陷和人类肿瘤放射增敏

• 批准号: 6626744
• 负责人: TIMOTHY J KINSELLA
• 金额: $ 22.67万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-25 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626744
• 关键词: DNA damage; DNA repair; adduct; athymic mouse; bromodeoxyuridine; cell cycle; cell growth regulation; colorectal neoplasms; cytotoxicity; drug resistance; gene mutation; high performance liquid chromatography; idoxuridine; ionizing radiation; neoplasm /cancer genetics; nucleoside analog; radiation sensitivity; thymidine; tissue /cell culture; western blottings

Mutations or loss of expression of DNA mismatch repair (MMR) genes especially MLH1, MSH2 and PMS2) have been found with an increasing frequency in many types of sporadic human colon cancers, along with the causal relationship previously observed with hereditary nonpolyposis colorectal cancers (HNPCC). MMR-deficient human tumor cells have demonstrated resistance to many different types of clinically active chemotherapy drugs, pointing out the potential need for new treatment approaches for MMR-deficient tumors. The observed drug resistance in MMR-deficient cells may be attributed to "damage tolerance", an inability of the cell to detect or respond to chemotherapy-induced DNA damage. The purine analog, 6-thioguanine (6-TG) is used experimentally to define the "damage tolerant" phenotype of MMR-deficient cells. Recent data from our laboratory suggest that MLH1-, MMR-deficient cells have reduced clonogenic survival and reduced G2/M arrest following ionizing radiation (IR) exposures. Additionally, we found that MLH1- (and, preliminarily, MSH2-), MMR-deficient cells show "damage tolerance" following exposures to the halogenated thymidine (dThd) analogs, bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd); resulting in greater than 2-3 fold higher levels of incorporated drug into DNA, compared to genetically-matched wild type (MMRT) tumor cells. Consequently, we found that treatment with BrdUrd or IdUrd prior to IR resulted in a significant enhancement in IR-induced cytotoxicity (radiosensitization) in MLH1-, MMR-deficient cells, but not in the matched MLH1+, MMR-proficient tumor cells. We hypothesize that it may be possible to develop treatment strategies to target MMR-deficient human cancers using halogenated thymidine analog-mediated radiosensitization. These preclinical studies will be the first step in the development of a Phase I/Il tumor-specific treatment strategy to target MMR-deficient tumors.

DNA错配修复（MMR）基因（尤其是MLH 1、MSH 2和PMS 2）的突变或表达缺失在许多类型的散发性人类结肠癌中已被发现具有增加的频率，沿着先前观察到的与遗传性非息肉病性结直肠癌（HNPCC）的因果关系。MMR缺陷的人类肿瘤细胞已经表现出对许多不同类型的临床活性化疗药物的抗性，指出了对MMR缺陷肿瘤的新治疗方法的潜在需求。 在MMR缺陷细胞中观察到的耐药性可能归因于“损伤耐受性”，即细胞不能检测或响应化疗诱导的DNA损伤。 嘌呤类似物6-硫代鸟嘌呤（6-TG）在实验上用于定义MMR缺陷细胞的“损伤耐受”表型。我们实验室的最新数据表明，MLH 1，MMR缺陷的细胞具有降低的克隆存活率和降低电离辐射（IR）暴露后的G2/M期阻滞。 此外，我们发现MLH 1-（和初步的MSH 2-）、MMR缺陷细胞在暴露于卤代胸苷（dThd）类似物、溴脱氧尿苷（BrdUrd）或碘脱氧尿苷（IdUrd）后显示出“损伤耐受性”;与遗传匹配的野生型（MMRT）肿瘤细胞相比，导致掺入DNA中的药物水平高出2-3倍。因此，我们发现在IR之前用BrdUrd或IdUrd处理导致MLH 1-、MMR缺陷细胞中IR诱导的细胞毒性（放射增敏）显著增强，但在匹配的MLH 1+、MMR-熟练的肿瘤细胞中不显著增强。 我们推测，它可能是可能的开发治疗策略，以针对MMR缺陷的人类癌症使用卤代胸苷类似物介导的放射增敏。 这些临床前研究将是开发针对MMR缺陷型肿瘤的I/II期肿瘤特异性治疗策略的第一步。

项目成果

DNA mismatch repair (MMR) mediates 6-thioguanine genotoxicity by introducing single-strand breaks to signal a G2-M arrest in MMR-proficient RKO cells.

• 发表时间: 2003-06
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: T. Yan;S. E. Berry;Anand B. Desai;T. Kinsella

CHK1 and CHK2 are differentially involved in mismatch repair-mediated 6-thioguanine-induced cell cycle checkpoint responses.

CHK1 和 CHK2 不同程度地参与错配修复介导的 6-硫鸟嘌呤诱导的细胞周期检查点反应。

• 发表时间: 2004
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Yan,Tao;Desai,AnandB;Jacobberger,JamesW;Sramkoski,RMichael;Loh,Tamalette;Kinsella,TimothyJ
• 通讯作者: Kinsella,TimothyJ

Both DNA topoisomerase II-binding protein 1 and BRCA1 regulate the G2-M cell cycle checkpoint.

DNA 拓扑异构酶 II 结合蛋白 1 和 BRCA1 均调节 G2-M 细胞周期检查点。

• 发表时间: 2003
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Yamane,Kazuhiko;Chen,Junjie;Kinsella,TimothyJ
• 通讯作者: Kinsella,TimothyJ