ANTIMETABOLITE SELECTIVITY--REGIONAL MODULATION

这个项目的总体目标是研究细胞效应 以及卤代嘧啶的辐射相互作用， 肝内恶性肿瘤治疗的知识， 胰腺癌 将成为调查重点的药物是 溴脱氧尿苷（BUDR）、氟脱氧尿苷（FUDR）和氟尿嘧啶 （FU）。 在本授标期间开展的工作表明， 化疗剂FUDR和FU在使用时是放射增敏剂 并改善胸苷类似物的功效， 放射增敏剂BUDR通过增加其掺入DNA的 肿瘤细胞 这一建议旨在获得对该机制的新见解， 这些代理人的行动，并应用我们以前获得的知识， 临床前研究到临床试验。 项目% 1最近扩展 关于氟嘧啶诱导细胞毒性基础的发现 和DNA损伤，并提出测试假设，即：a）活动 dUTR和/或尿嘧啶-DNA-糖基化酶可能是限制性决定因素 对于人类结肠直肠肿瘤细胞对高浓度 氟嘧啶类药物（如区域给药期间使用的药物），以及 B）在某些肿瘤细胞中，对氟嘧啶的抗性可能是 通过同时给予dUTR抑制剂来克服。 项目2旨在 确定BUDR影响辐射诱导DNA的机制 在个体染色体和亚染色体水平上的损伤， 使用脉冲场凝胶电泳和荧光原位 杂交方法 目标是确定BUDR公司是否改变 辐射产生的DNA损伤的类型和数量， 与辐射敏感性最密切相关的病变。 项目 3将系统地研究肝损伤的影响（丧失 肝细胞质量与功能丧失）对FU处置动力学的影响 和BUDR后系统和区域管理。 中的研究 项目3将与拟定的临床研究直接相关 涉及肝功能下降患者的局部药物输注。 对于临床研究（项目4），采取的方法将是生成 将BUDR与精确的， 三维计划外照射。 活检研究将 进行肿瘤和正常组织对BUDR的摄取（通过GC/MS测定和 通过免疫组织化学测定）按照相关的输注时间表给予 （肝动脉用于肝肿瘤，静脉内IV用于胰腺肿瘤） 以确定是否发生显著（>5%）掺入。 基于 在我们的临床前研究中，将同时使用BUDR输注， 肝肿瘤和BUDR输注与“洗脱期”将 在胰腺癌中进行研究，以将肿瘤最大化至剂量限制正常水平 药物的组织摄取。 总而言之，该提案确定了一种促进基本 了解这些药物，同时结合药理学数据， 先进的技术，合理地生成独特的临床协议 在治疗这些常见的， 异常致命的胃肠道恶性肿瘤

The overall goal of this program project is to study the cellular effects and radiotherapeutic interactions of the halopyrimidines and to apply such knowledge to the treatment of intrahepatic malignancies and pancreatic cancer. The drugs that will be the focus of investigation are bromodeoxyuridine (BUDR), fluorodeoxyuridine (FUDR), and fluorouracil (FU). The work performed during the current award period has shown that the chemotherapeutic agents FUDR and FU are radiosensitizers when used alone and improve the efficacy of the thymidine analog and radiosensitizer BUDR by increasing its incorporation into the DNA of tumor cells. this proposal seeks to gain new insights into the mechanism of action of these agents and to apply knowledge gained in our previous preclinical studies to clinical trials. Project 1 extends recent findings concerning the basis for fluoropyrimidine-induced cytotoxicity and DNA damage, and proposes to test hypotheses that: a) the activities of dUTPase and/or uracil-DNA-glycosylase may be the limiting determinants for sensitivity of human colorectal tumor cells to high concentrations of fluoropyrimidines (as are applied during regional administration), and b) in certain tumor cells, resistance to fluoropyrimidines may be overcome by coadministration of a dUTPase inhibitor. Project 2 seeks to determine the mechanism by which BUDR affects radiation induced DNA damage at the individual chromosomal and subchromosomal level through the use of pulsed field gel electrophoresis and fluorescence in situ hybridization. The goals are to determine if BUDR incorporation alters the type and number of DNA lesions produced by radiation and to identify the lesions most closely associated with radiation sensitivity. Project 3 will systematically study the effect of liver impairment (loss of hepatocyte mass vs. loss of function) on the disposition kinetics of FU and BUDR after systemic and regional administration. The studies in Project 3 will have direct relevance to proposed clinical studies involving regional drug infusion in patients with reduced liver function. for clinical studies (Project 4), the approach taken will be to generate regional chemo-radiosensitization regimens combining BUDR with precise, 3-D planned focal external beam radiotherapy. A biopsy study will be conducted of tumor and normal tissue uptake of BUDR (by GC/MS assay and by immunohistochemical assay) given on a relevant infusional schedule (hepatic arterial for hepatic and intravenous IV for pancreatic tumors) to determine whether significant (>5%) incorporation occurs. Based upon our preclinical studies, a concurrent BUDR infusion will be used in hepatic tumors and a BUDR infusion with a "washout" period will be studied in pancreatic cancers to maximize tumor to dose-limiting normal tissue uptake of drug. In summary, this proposal defines an approach furthering basic understanding of these agents while combining pharmacologic data with sophisticated technology to rationally generate unique clinical protocols with potentially improved potency in the treatment of these common, exceptionally lethal GI malignancies.