RADIOSENSITIZATION BY HALOGENATED THYMIDINE ANALOGS

描述：此修订版（A1）竞争性赠款续期请求支持 在体外和体内实验室中继续进行为期3年的研究 人肿瘤放射抗性细胞系及其相关因素的研究 使用新方法在人类和小鼠正常组织中进行临床前测试 卤代胸苷（dThd）对人肿瘤放射增敏作用的研究 类似物（BrdUrd; IdUrd）和相关的嘧啶酮化合物。 基于 根据本补助金产生的信息，我们建议调查3 在这次赠款更新的具体目标，以进一步提高治疗收益 人类肿瘤放射增敏作用。 首先，我们的体外和体内研究 提示同时使用直接的（5 ′-氨基-5 ′-脱氧胸苷， 5 '-AdThd）或间接（羟基脲，HU）TK活性调节剂， dThd类似物可以选择性地增强肿瘤放射增敏作用， 显著增加正常组织毒性。 我们建议进一步 表征这些TK的细胞和生化相互作用 调节剂和卤代dThd类似物以增强肿瘤 在特定目标#1下的放射增敏。 第二，我们将测试 假设人类肿瘤中TK调节（去调节）的差异 与正常组织相比， 被利用来选择性地增加药物（BrdUrd，IdUrd）活化，DNA 在放射抗性肿瘤中的掺入和随后的放射增敏作用 体外和体内（具体目标#2）。 最后，在具体目标#3下，我们 建议继续进行临床前试验， 5-碘-2-嘧啶酮-2 '脱氧核糖（EPdR）作为口服（p.o.）生物利用 IdUrd介导的放射增敏作用的前药 经口接种人肿瘤异种移植物的小鼠IPdR被迅速吸收， 有效转化为IdUrd，主要是B肝醛 氧化酶，导致高血浆IdUrd水平长达2-3小时后， P.O.推注。 与6天的口服疗法相比。大剂量或连续输注 最大耐受剂量下的IdUrd，IPdR（p.o. QD x 6）导致 改善的治疗增益，如肿瘤细胞% DNA掺入和增殖细胞中DNA掺入%的降低 正常组织

DESCRIPTION: This revised (A1) competitive grant renewal requests support for an additional 3-year period to continue in vitro and in vivo laboratory investigations in radioresistant human tumor cell lines and correlative pre-clinical testing in human and mouse normal tissues using new approaches to human tumor radiosensitization with the halogenated thymidine (dThd) analogs (BrdUrd; IdUrd) and related pyrimidinone compounds. Based on information generated in the present grant, we propose to investigate 3 specific aims in this grant renewal to further improve the therapeutic gain of human tumor radiosensitization. First, our in vitro and in vivo studies suggest that the concomitant use of direct (5'-amino-5'deoxythymidine, 5'-AdThd) or indirect (hydroxyurea, HU) modulators of TK activity with the dThd analogs can selectively enhance tumor radiosensitization without significantly increased normal tissue toxicities. We propose to further characterize the cellular and biochemical interactions of these TK modulators and the halogenated dThd analogs to enhance tumor radiosensitization under Specific Aim #1. Second, we will test the hypothesis that differences in the (de)regulation of TK in human tumors compared to normal tissues and in differential TK induction following I can be exploited to selectively increase drug (BrdUrd, IdUrd) activation, DNA incorporation and subsequent radiosensitization in radioresistant tumors in vitro and in vivo (Specific Aim #2). Finally, under Specific Aim #3, we propos to continue pre-clinical testing of 5-iodo-2-pyrimidinone-2'deoxyribose (EPdR) as an orally (p.o.) bioavailable prodrug for IdUrd-mediated radiosensitization We have shown in athymic nude mice with human tumor xenografts that p.o. IPdR is rapidly absorbed and undergoes efficient conversion to IdUrd, principally b hepatic aldehyde oxidase, resulting in high plasma IdUrd levels for up to 2-3 hrs following a p.o. bolus. Compared to a 6-day course of p.o. bolus or continuous infusion IdUrd at the maximum tolerated dose, IPdR (p.o. QD x 6) resulted in an improved therapeutic gain as evidenced by both an increase in tumor cell % DNA incorporation and a decrease in % DNA incorporated in proliferating normal tissues.