DNA DAMAGE AND REPAIR IN BRAIN TUMORS

脑肿瘤中的 DNA 损伤和修复

• 批准号: 6101543
• 负责人: WILLIAM J BODELL
• 金额: $ 8.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-08 至 2000-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6101543
• 关键词: DNA damage; DNA repair; adduct; alkyltransferase; antineoplastics; biopsy; brain neoplasms; bromodeoxyuridine; cancer registry /resource; colorimetry; crosslink; glioma; guanine analog; human subject; immunocytochemistry; lymphocyte; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer relapse /recurrence; nitrosourea; phosphorus; radionuclides; radiosensitizer; ultraviolet spectrometry

Chloroethylnitrosoureas (CENUs) are a group of chemotherapeutic agents used in conjunction with radiation therapy for the treatment of brain tumors. The goal of our research is to investigate the roles of DNA damage and repair in the cellular response of brain tumors to treatment with these and other agents. The DNA repair enzyme O/6-alkylguanine-DNA alkyltransferase (O/6-AT) has been shown to play an important role in determining cellular resistance to CENUs, although its role in determining the response of tumors to treatment with CENUs has not been determined. In addition, the extent of DNA damage in the lymphocytes of patients undergoing treatment with CENUs may be an indicator of the extent of DNA damage in the tumor being treated. We propose that measurement of the levels of O/6-AT in surgical glioma specimens and of DNA alkylation in patients' lymphocytes after treatment with CENUs may be useful indicators of patients' responses to the treatment. In parallel the halogenated pyrimidines 5-bromo-2'deoxyuridine (bromodeoxyuridine; BUdR) and 5-iodo- 2'deoxyuridine (iododeoxyuridine; IUdR) are well-established radiosensitizers in vitro. For the successful use of these agents as radiosensitizers in the treatment of patients with brain tumors, an understanding of their incorporation into DNA is required. To better understand the relationships between DNA damage and repair and response to treatment with CENUs and radiosensitizers, our specific aims are: 1) to measure the level of O/6-AT in primary brain tumors and determine whether increased O/6-AT levels correlate inversely with clinical efficacy of treatment with nitrosoureas; 2) to compare the levels of O/6-AT in primary and recurrent brain tumors; 3) to measure the levels of N/7-(2- hydroxyethyl)guanine and N/7-(2-chloroethyl)guanine in DNA isolated from lymphosytes of patients treated with l,3,bis(2-chloroethyl)-1-nitrosourea (BCNU); 4) to develop and apply the 32/P-postlabeling technique for the detection of the cross-link 1-[N/3-2'deoxycytidyl], 2-[N/1- deoxyguanosinyl]-ethane in DNA isolated from the lymphocytes of patients treated with BCNU; 5) to determine whether the levels of N/7-2- hydroxyethyl)guanine and N/7-(2-chloroethyl)guanine and 1-[N/3- 2'deoxycytidyl], 2-[N/1-deoxyguanosinyl]-ethane correlate with clinical efficacy of treatment with nitrosoureas; and, 6) to measure the percent substitution of BUdR and IUdR for thymidine in brain tumors.

氯乙基亚硝基脲（CENUs）是一组化学治疗剂 与放射疗法一起用于治疗脑部疾病 肿瘤的 我们研究的目的是研究DNA在 脑肿瘤细胞对治疗反应中的损伤和修复 与这些和其他代理人。 DNA修复酶O/6-烷基鸟嘌呤-DNA 烷基转移酶（O/6-AT）已被证明在 决定细胞对CENUs的抗性，尽管它在决定 肿瘤对CENUs治疗的反应尚未确定。 此外，患者淋巴细胞中DNA损伤的程度 接受CENUs治疗可能是DNA损伤程度的指标， 在治疗的肿瘤中的损伤。 我们建议， 脑胶质瘤手术标本中O/6-AT水平和脑胶质瘤中DNA烷基化水平 用CENUs治疗后患者的淋巴细胞可能是有用的指标 病人对治疗的反应。 与此同时， 嘧啶类5-溴-2 '-脱氧尿苷（溴脱氧尿苷; BUdR）和5-碘- 2 '脱氧尿苷（碘脱氧尿苷; IUdR）是公认的 体外放射增敏剂。 为了成功地使用这些药物， 放射增敏剂治疗脑肿瘤患者， 需要了解它们与DNA的结合。 更好地 理解DNA损伤和修复之间的关系， 使用CENUs和放射增敏剂治疗，我们的具体目标是：1） 测量原发性脑肿瘤中O/6-AT的水平， O/6-AT水平的增加与 2）比较原发性肝癌患者O/6-AT水平， 和复发性脑肿瘤; 3）测量N/7-（2- 在分离的DNA中的N-（2-羟乙基）鸟嘌呤和N-（7-（2-氯乙基）鸟嘌呤 用1，3-双（2-氯乙基）-1-亚硝基脲治疗的患者的淋巴系统 （BCNU）; 4）发展和应用32/P-后标记技术， 检测交联1-[N/3- 2 '脱氧胞苷基]，2-[N/1- 从患者淋巴细胞分离的DNA中的脱氧鸟苷基]-乙烷 用BCNU处理; 5）确定N/7-2- N-（2-羟乙基）鸟嘌呤和N/7-（2-氯乙基）鸟嘌呤和1-[N/3-（2-羟乙基）鸟嘌呤]。 2-[N/1-脱氧鸟苷基]-乙烷与临床 用亚硝基脲治疗的功效;以及，6）测量 脑肿瘤中BUdR和IUdR取代胸苷。