Human Tumor Radiosensitization by IUdR and IPdR

IUdR 和 IPdR 对人类肿瘤放射增敏

• 批准号: 6473086
• 负责人: TIMOTHY J KINSELLA
• 金额: $ 25.1万
• 依托单位: UNIVERSITY HOSPITALS OF CLEVELAND
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6473086
• 关键词: DNA repair; analog; athymic mouse; clinical trial phase I; cytotoxicity; deoxyribose; disease /disorder model; drug administration rate /duration; drug metabolism; drug screening /evaluation; ferrets; high performance liquid chromatography; human therapy evaluation; immunocytochemistry; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; neoplastic cell; nonhuman therapy evaluation; oral administration; oral mucosa; pharmacokinetics; prodrugs; radiation sensitivity; radiosensitizer; thymidine; tissue /cell culture

The overall aim of this revised 4 year competitive renewal grant (years 9-12) is to better understand the biochemical, cellular and pharmacological mechanisms of human tumor radiosensitization, using relevant in vivo experimental models, by the halogenated thymidine analog, iododeoxyuridine (IudR) and its prodrug. We also propose to design and implement two initial Phase I clinical trials to increase the therapeutic index for human tumor radiosensitization by the prodrug 5- iodo-2-pyrimidinone-2'-deoxyribose (IPdR). Two specific aims are proposed in this revised proposal. In Specific Aim 1, we propose to continue our in vivo studies of 5-iodo- 2-pyrimidinone-2'-deoxyribose (IPdR) as an oral (po) prodrug for IudR- mediated human tumor radiosensitization. The major hypothesis to be tested in Aim 1 is that more frequent (BID/TID) daily dosing for longer periods (up to 28 days) of po IPdR will further improve the therapeutic index for human tumor radiosensitization, based on our current understanding of IPdR metabolism, pharmacokinetics and systemic toxicities. We will also assess the efficacy of po IpdR as an in vivo radiosensitizer using mice bearing xenografts from genetically-matched human tumor and derived murine embryonic cell lines which differ in MMR status for the two principal MMR genes/proteins recognized in hereditary (HNPCC) and sporadic human cancers (MLH1 and MSH2). In Specific Aim 2, we propose to initiate the first two Phase I clinical and pharmacokinetic studies of IpdR as a radiosensitizing drug. We hypothesize that po IpdR in humans will result in higher (but transient) plasma IudR levels, higher levels of IudR-DNA incorporation in tumor, and less systemic toxicity to one marrow and the GI mucosa which should lead to an improved therapeutic gain and more effective tumor radiosensitization compared to our prior results with continuous infusion IudR.

这项修订后的4年竞争性更新赠款的总体目的（9-12年）是通过使用卤素类似物类似物，碘氧化胆碱（IUDR）和其Prodrug的卤素实验模型，更好地了解人类肿瘤放射敏化的生化，细胞和药理机制。我们还建议设计和实施两项初始I期临床试验，以增加前药5-iodo-2-吡啶酮-2'-脱氧核糖（IPDR）的治疗指数。在这项修订的提案中提出了两个具体目标。在特定目标1中，我们建议继续对5-碘-2-二吡啶酮-2'-脱氧核糖（IPDR）的体内研究，作为IUDR介导的人类肿瘤放射敏化的口服（PO）前药。在AIM 1中要测试的主要假设是，基于我们当前对IPDR代谢，药代动力学和系统性毒性的理解，每天更频繁（BID/TID）每日剂量更长（长达28天）的PO IPDR长期（长达28天）将进一步改善人类肿瘤放射敏化的治疗指数。我们还将使用在遗传匹配的人类肿瘤和衍生的鼠类胚胎细胞系中轴承异种移植的小鼠来评估PO IPDR作为体内放射敏剂的功效，这些小鼠在两个主要MMR基因/蛋白质的MMR状态上有所不同，在遗传性（HNPCC）和孢子虫人的人类Cancers（MLH）中（MMR基因/蛋白）（MMR基因/蛋白在特定的目标2中，我们建议启动IPDR作为放射敏化药物​​的前两个I期临床和药代动力学研究。我们假设人类的PO IPDR将导致肿瘤中的IUDR水平较高（但短期）IUDR水平，肿瘤中的IUDR-DNA水平较高，并且对一根骨髓的系统性毒性较小，而GI粘膜的系统性较小，而GI粘膜应带来改善的治疗性增益和更多有效的Tumor tumor radiosemenitiations，与我们先前的结果相比，它与Continufius Infusif Infusif Infusif Infusif Infusif Iudr相比。