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.

氯乙基亚硝脲(Cenus)是一类化疗药物。 与放射治疗联合用于治疗脑部疾病 肿瘤。我们研究的目标是研究DNA的作用 脑肿瘤细胞治疗反应中的损伤与修复 和这些和其他特工一起。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 确定细胞对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感染程度的一个指标。 正在治疗的肿瘤中的损伤。我们建议对 脑胶质瘤手术标本中O/6-AT和DNA烷基化水平的研究 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。平行的卤化 5-溴-2‘-脱氧尿苷和5-碘-2’-脱氧尿苷 2‘-脱氧尿嘧啶核苷(Idedodeoxuridine；IUdR)是公认的 体外放射增敏剂。为了成功地将这些代理用作 放射增敏剂在脑肿瘤患者治疗中的应用 需要了解它们在DNA中的结合情况。为了更好地 了解DNA损伤和修复之间的关系以及对 使用环磷酰胺和放射增敏剂治疗，我们的具体目标是：1) 检测原发性脑肿瘤组织中O/6-AT水平 O/6-AT水平升高与临床疗效呈负相关 亚硝脲治疗；2)比较高血压病患者O/6-AT水平 3)测定N/7-(2-)的水平。 日本血吸虫DNA中的羟乙基)鸟嘌呤和N/7-(2-氯乙基)鸟嘌呤 L，3，二(2-氯乙基)-1-亚硝脲治疗患者的淋巴细胞 (4)开发和应用32/P-后标记技术 1-[N/3-2‘-脱氧胞苷]，2-[N/1- 患者淋巴细胞DNA中的脱氧鸟苷-乙烷 用BCNU治疗；5)测定N/7-2- 羟乙基)鸟嘌呤和N/7-(2-氯乙基)鸟嘌呤和1-[N/3- 2‘-脱氧胞苷、2-[N/1-脱氧鸟苷]-乙烷与临床的关系 亚硝脲治疗的疗效；以及，6)测量 在脑肿瘤中用BUDR和IUdR替代胸腺嘧啶核苷