Human Tumor Radiosensitization by IUdR and IPdR

这项修订后的4年竞争续期补助金(第9-12年)的总体目标是利用相关的体内实验模型，更好地了解卤代胸苷类似物碘脱氧尿苷(IudR)及其前体药物对人类肿瘤放射增敏的生化、细胞和药理学机制。我们还建议设计和实施两个初步的I期临床试验，以提高前药5-碘-2-嘧啶酮-2‘-脱氧核糖(IPdR)对人类肿瘤放射增敏的治疗指数。在这项修订的提案中提出了两个具体目标。在具体目标1中，我们建议继续我们的体内研究，5-碘-2-嘧啶酮-2‘-脱氧核糖(IPdR)作为口服(Po)前药，用于IudR介导的人肿瘤放射增敏。在目标1中要测试的主要假设是，基于我们目前对IPdR新陈代谢、药代动力学和全身毒性的理解，更频繁(BID/TID)的较长时间(长达28天)的po IPdR每日剂量将进一步改善人类肿瘤放射增敏的治疗指数。我们还将评估po IpdR作为体内放射增敏剂的有效性，使用携带来自基因匹配的人类肿瘤的异种移植的小鼠和衍生的小鼠胚胎细胞系，这些细胞系在遗传性(HNPCC)和散发性人类癌症(MLH1和MSH2)中识别的两个主要MMR基因/蛋白的MMR状态不同。在具体目标2中，我们建议启动IpdR作为放射增敏药物的前两个I期临床和药代动力学研究。我们假设，在人类中，口服IpdR将导致更高的(但短暂的)血浆IudR水平，更高的IudR-DNA在肿瘤中的掺入水平，以及对骨髓和胃肠道粘膜的全身毒性较小，这将导致与我们之前的持续输注IudR的结果相比，这将导致更好的治疗收益和更有效的肿瘤放射增敏。

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.