DNA ADDUCTS FORMED DURING BRAIN TUMOR THERAPY

脑肿瘤治疗过程中形成的 DNA 加合物

• 批准号: 2806097
• 负责人: WILLIAM J BODELL
• 金额: $ 20.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2806097
• 关键词: adduct; alkylating agents; analytical chemistry; antineoplastics; antiserum; brain neoplasms; carmustine; chemical conjugate; crosslink; dacarbazine; deoxyguanosine; dosage; drug administration rate /duration; drug administration routes; electrochemistry; high performance liquid chromatography; immunofluorescence technique; immunologic assay /test; laboratory rat; method development; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nuclear magnetic resonance spectroscopy; procarbazine; xenotransplantation

Each year there are approximately 50,000 newly diagnosed brain tumors. Chemotherapy is established to be important in the treatment of newly diagnosed and recurrent brain tumors. Laboratory based studies have established that DNA alkylation plays a key role in the initiation of cellular death by chemotherapeutic agents. In order to achieve a better understanding of this process in brain tumor therapy; we propose to measure the formation of DNA abducts in intracerebral (ic.) Tumors treated with alkylating chemotherapeutic agents currently being evaluated for the treatment of brain tumors. To achieve this goal we propose to Aim 1. Optimize a dissociation enhanced lanthanide fluoroimmunoassay (DELFIA) method fo the quantitatation of O6 -methyldeoxguanosine (O6 -MedG). The levels of N7 -methyldeoxguanosine (N7 - MeG) will be determined by electrochemical detection. We will measure the levels of O6 -MedG and N7 -MeG formed in U-87MG cells grown as ic. Tumors in athymic rats treated with temozolamide (TMZ). In these tumors, we will investigate the relationships between levels of O6 -MedG and N7-MeG formed and route of administration, treatment dose and agent and number of treatments. The levels of these alkylation products formed in the ic. tumors will be compared with the levels formed in the contralateral hemisphere and in normal tissues. These methodologies will provide ea unique approach for preclinical analysis of alkytating chemotherapeutic agents in treatment of brain tumors. Aim 2. We will develop a poly clonal antiserum to the dG-dC crosslink (1- [N3-2'deoxycytidly], 2-[N1-2; -DEOXYGUANOSYL]-Ethane) formed by BCNU. Using this antiserum, we will optimize a DELFIA method for the quantitation of the dG-dC crosslink. Aim 3 Investigate the formation of the dG-dC crosslink, O6-(2-hydroxy ethyl) deoxyguanosine (O6- HOEtdG) and N7 - (2-hydroxy ethyl) deoxyguanosine N7-HOEtG. Athymic rats bearing U-87MG ic. Tumors will be treated with either BCNU SarCNU or mitozolamide. The formation of dG-dC crosslink, O6-HOEtdG and N7-HOEtG will be quantitated. We will examine the relationships between levels of these alkylation products and treatment agent, dose and. Number of treatment. These studies will be the first to investigate the formation of BCNU derived DNA abducts in a ic. Brain tumor model.

每年大约有50,000个新诊断的脑肿瘤。 化学疗法在治疗新诊断和复发性脑肿瘤方面很重要。 基于实验室的研究已经确定，DNA烷基化在化学治疗剂启动细胞死亡中起关键作用。 为了更好地了解脑肿瘤疗法的这一过程；我们建议测量在脑内（IC。）肿瘤中用烷基化化学治疗剂治疗的脑肿瘤中DNA绑架的形成，目前正在评估治疗脑肿瘤。为了实现这一目标，我们提出了目标1。优化O6 -Methyldeoxguanosine（O6 -Medg）定量的分离增强型灯笼氟免疫测定法（Delfia）方法。 N7-甲基氧鸟苷（N7 -MEG）的水平将由电化学检测确定。 我们将测量以IC生长的U -87MG细胞中形成的O6 -MEDG和N7 -MEG的水平。用替莫唑胺（TMZ）处理的无胸腺大鼠肿瘤。 在这些肿瘤中，我们将研究形成的O6 -MedG和N7 -MEG水平与给药途径，治疗剂量和药物以及治疗数量之间的关系。 这些烷基化产物的水平在IC中形成。 将肿瘤与对侧半球和正常组织中形成的水​​平进行比较。 这些方法将为EA提供独特的方法，用于临床前分析藻类化学治疗剂在治疗脑肿瘤中。 AIM 2。我们将开发一个由BCNU形成的DG-DC交叉链接（1- [N3-2'DeoxyCytidly]，2- [N1-2; -DeoxyGuanosyl]甲烷）。使用此抗血清，我们将优化一种用于定量DG-DC交叉链接的Delfia方法。 AIM 3研究了DG-DC交叉链接O6-（2-羟基乙基）脱氧鸟苷（O6- HOETDG）和N7-（2-羟基乙基）脱氧鸟苷N7-Hoetg的形成。 带有U-87MG IC的无胸腺大鼠。肿瘤将用BCNU SARCNU或硅酚治疗。 将定量DG-DC交叉链接，O6-HOETDG和N7-HOETG的形成。 我们将研究这些烷基化产品水平与治疗剂，剂量和剂量之间的关系。治疗次数。 这些研究将是第一个研究IC中BCNU衍生的DNA绑架的形成的研究。脑肿瘤模型。