DEVELOPMENT OF 9-SUBSTITUTED BG DERIVATIVES

9-取代BG衍生物的开发

• 批准号: 6347328
• 负责人: S C SCHOLD
• 金额: $ 9.81万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347328
• 关键词: DNA repair; alkylating agents; alkyltransferase; antineoplastics; athymic mouse; brain neoplasms; carmustine; disease /disorder model; drug administration rate /duration; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme inhibitors; guanine analog; guanosine; high performance liquid chromatography; laboratory rat; neoplastic cell; pharmacokinetics; solvents; tissue /cell culture; xenotransplantation

The DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT)mediates resistance to BCNU and related alkylating agents in human tumors by removing O6-alkylguanine DNA adducts produced by these drugs. Inibitors of AGT activity, such as O6-benzylguanine (BG), increase sensitivity to these alkylating drugs and are potentially important modulators of several common anti-neoplastic drugs. One limitation of BG is that its AGT-inhibiting activity is non-specific so that normal cells and tissues in addition to tumors, are sensitized to DNA damaging agents. The central hypothesis of this program is that the 9-substituted derivatives of BG will be more effective than BG because of more favorable pharmacologic characteristics and relatively selective activation in certain tissues and tumors. Preliminary data indicate that two such analogs, O6-benzyl-2'- deoxyguanosine and O6-benzylguanosine, are effective in inhibiting AGT in human tumor xenografts even though they are substantially less potent AGT inhibitors than BG in vitro. Our data support the idea that this enhanced AGT inhibition in both rats and human brain tumor xenografts in athymic mice is due to greater systemic availability of the parent compound and, more importantly, to site-specific activation of the parent compound to BG and O6-benzyl-8-oxo-guanine, which are two metabolites with considerable AGT-inhibiting activity. These data encourage additional screening of 9- substituted BGs to identify more potent and more site specific AGT inhibitors and to establish the mechanism of their enhanced inhibitory activity in vivo. We also propose to optimize the use of these inhibitors by adjusting doses and administration schedules. Our aims are to; 1) determine the extent and duration of AGT suppression in human brain tumor xenografts and normal organs in tumor-bearing athymic mice after administration of 9-substituted BGs; 2) identify the principal metabolites of 9-substituted BGs in rats, athymic mice, and human tumor xenografts; 3) determine the relationship between the pharmacokinetics and metabolism of 9-substituted BGs and the extent and duration of AGT inhibition in brain tumor xenografts and normal organs, and 4) optimize the BCNU potentiating effects of the 9-substituted BGs against human brain tumor xenografts. We expect to identify potent AGT inhibitors with enhanced therapeutic indices and selectivity against brain neoplasms.

DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）介导 通过人类肿瘤中对BCNU和相关烷基化剂的抗性 去除这些药物产生的O6-烷基鸟嘌呤DNA加合物。 罪魁祸首 AGT活性，例如O6-苄基圭氨酸（BG），会增加对这些的敏感性 烷基化药物，是几种常见的潜在重要调节剂 抗塑性药物。 BG的一个限制是它的AGT抑制作用 活性是非特异性的，因此除了正常细胞和组织以外 肿瘤对DNA破坏剂的敏感。 中心假设 该程序是BG的9个取代的衍生物将更多 由于具有更有利的药理特性，比BG有效 并在某些组织和肿瘤中相对选择性激活。 初步数据表明，两个这样的类似物O6-苯唑-2'-- 脱氧鸟苷和O6-苯二唑烷糖苷可有效抑制AGT 即使人类肿瘤异种移植物的有效AGT差得多 抑制剂比体外BG。 我们的数据支持了这一想法 大鼠和人脑肿瘤异种移植的AGT抑制作用 小鼠是由于父母化合物的全身性可用性较大，并且 更重要的是，将母体化合物特定于位点激活到BG 和O6-苯唑-8-氧气瓜氨酸，它们是两个代谢物，相当大 AGT抑制活性。 这些数据鼓励对9-的额外筛选 取代BGS以识别更有效，更特定的特定地点AGT 抑制剂并确定其增强抑制作用的机制 体内活动。 我们还建议优化这些抑制剂的使用 通过调整剂量和管理时间表。 我们的目标是 1） 确定人脑肿瘤中AGT抑制的程度和持续时间 异种移植物和含有肿瘤的无胸腺小鼠的正常器官 给予9个取代的BGS； 2）确定主要代谢物 大鼠，无胸腺小鼠和人类肿瘤异种移植物中的9个取代的BG； 3） 确定药代动力学和代谢之间的关系 9个取代的BGS以及大脑AGT抑制的程度和持续时间 肿瘤异种移植物和正常器官，以及4）优化BCNU增强 9个取代的BGS对人脑肿瘤异种移植的影响。 我们 希望通过增强的治疗指数鉴定有效的AGT抑制剂 和针对脑肿瘤的选择性。