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.

氯乙基硝酸（Cenus）是一组化学治疗剂 与放射疗法结合使用以治疗大脑 肿瘤。 我们研究的目的是研究DNA的作用 脑肿瘤对治疗的细胞反应的损害和修复 与这些代理商和其他代理商。 DNA修复酶O/6-烷基鸟嘌呤-DNA 已显示烷基转移酶（O/6-AT）在 确定细胞对Cenus的抗性，尽管其在确定的作用 尚未确定肿瘤对用Cenus治疗的反应。 另外，患者淋巴细胞中DNA损伤的程度 接受Cenus治疗可能是DNA程度的指标 治疗肿瘤的损害。 我们提出了测量 手术胶质瘤标本中的O/6-AT水平和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 患者对治疗的反应。 并联卤代 嘧啶5-溴-2'Deoxyuridine（溴脱氧尿苷； BudR）和5-碘 - 2'Deoxyuridine（碘氧化尿苷； IUDR）是完善的 放射增强剂体外。 为了成功使用这些代理 放射敏剂在治疗脑肿瘤患者的治疗中 需要了解它们纳入DNA。 更好 了解DNA损伤与维修之间的关系以及对 用Cenus和放射敏剂处理，我们的具体目的是：1） 测量原发性脑肿瘤中O/6-AT的水平，并确定是否是否 O/6-AT水平的升高与临床功效成反比 硝基库治疗； 2）比较主要的O/6-AT级别 和复发性脑肿瘤； 3）测量N/7-的水平（2- 羟基乙基）鸟嘌呤和N/7-（2-氯乙基）鸟嘌呤在DNA中分离出来 用L，3，BIS（2-氯乙基）-1-硝基库治疗的患者的淋巴样 （BCNU）; 4）开发和应用32/p杆标签技术 检测1- [n/3-2'deoxycytidyl]的交联1- [N/1-- 从患者的淋巴细胞中分离的DNA中的脱氧鸟氨烷基] - 乙烷 用BCNU处理； 5）确定N/7-2-的水平是否 羟乙基）鸟嘌呤和N/7-（2-氯乙基）鸟嘌呤和1- [N/3-- 2'DeoxyCytidyl]，2- [N/1-脱氧瓜烷酰基] - 乙烷与临床相关 硝基库治疗的功效；和6）测量百分比 在脑肿瘤中取代BUDR和IUDR代替胸苷。