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: 6342224
• 负责人: TIMOTHY J KINSELLA
• 金额: $ 21.81万
• 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 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342224
• 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.

在许多类型的零星人类结肠癌中发现了DNA不匹配修复（MMR）基因特别是MLH1，MSH2和PMS2的突变或表达丧失，以及以前与遗传性非骨型结肠癌结肠癌（HNPCC）观察到的因果关系。缺乏MMR的人类肿瘤细胞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缺陷型肿瘤的新治疗方法的潜在需求。 观察到的MMR缺陷细胞中观察到的耐药性可能归因于“损伤耐受性”，这是该细胞检测或响应化学疗法诱导的DNA损伤的能力。 嘌呤类似物，6-硫代氨酸（6-TG）在实验上用于定义MMR缺陷细胞的“损伤耐受性”表型。我们实验室的最新数据表明，MLH1-缺陷型细胞在电离辐射（IR）暴露后降低了克隆生存的生存和降低的G2/M停滞。 此外，我们发现MMR缺陷的细胞在暴露于卤代胸腺胺（dthd）类似物，溴脱氧尿苷（BRDURD）或碘氧化尿苷（Idurd）之后，MMR缺乏细胞显示了MMR缺陷细胞的MLH1-（以及MSH2-）；与遗传匹配的野生型（MMRT）肿瘤细胞相比，导致掺入DNA的掺入中的2-3倍大于2-3倍。因此，我们发现在IR之前使用BRDURD或IDURD治疗会导致MLH1-，MMR缺陷细胞中IR诱导的细胞毒性（放射性化）的显着增强，但在匹配的MLH1+，MMR富含MMR的肿瘤细胞中没有显着增强。 我们假设有可能使用卤代胸腺胺类似物介导的放射敏化来制定治疗策略，以靶向MMR缺陷型人类癌。 这些临床前研究将是开发I/IL肿瘤特异性治疗策略以靶向MMR缺陷肿瘤的第一步。