RADIOSENSITIZATION BY HALOGENATED THYMIDINE ANALOGS

描述：此修订版(A1)竞争性授权续订请求支持 在体外和体内实验室中继续进行额外的3年 抗辐射人肿瘤细胞系及相关研究进展 使用新方法在人和小鼠正常组织中进行临床前测试 卤代胸苷(DThd)对人肿瘤的放射增敏作用 类似物(BrdUrd；IdUrd)和相关的嘧啶酮化合物。基于 ，我们建议调查3个 在这次赠款续期中的具体目标是进一步提高治疗收益 关于人类肿瘤放射增敏的研究。首先，我们的体外和体内研究 建议同时使用直接(5‘-氨基-5’-脱氧胸腺嘧啶核苷， 5‘-AdThd)或间接(羟基脲，Hu)调节TK活性 DThd类似物可以选择性地增强肿瘤的放射增敏，而不需要 显著增加正常组织的毒性。我们建议进一步 描述这些TK的细胞和生化相互作用 调节剂和卤代dThd类似物增强肿瘤 在特定目标下的放射增敏#1。第二，我们将测试 假设TK在人类肿瘤中的(去)调节不同 与正常组织相比，在差异性TK诱导下，我可以 被利用来选择性地增加药物(BrdUrd，IdUrd)的激活，DNA 放射抵抗肿瘤的掺入和随后的放射增敏 体外和体内(特定目标2)。最后，在具体目标3下，我们 建议继续进行临床前测试 5-碘-2-嘧啶酮-2‘-脱氧核糖(EPdR)口服(P.O.)生物利用度 IdUrd介导的放射增敏前药我们已在裸鼠体内展示 带人肿瘤异种移植的小鼠。知识产权迅速被吸收， 有效地转化为IdUrd，主要是b肝醛 氧化酶，导致血浆IdUrd水平升高，持续时间长达2-3小时 邮政总局丸剂。相比之下，6天的P.O课程。团注或持续输液 最大耐受量IdUrd(P.O.Qd x 6)导致了 治疗收益的改善，从肿瘤细胞百分比的增加可见一斑 DNA掺入和增殖过程中DNA掺入百分比的下降 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.