ANTIMETABOLITE SELECTIVITY--REGIONAL RX/MODULATION

这项提议的目标是发展更多的 肝肿瘤和高级别胶质瘤的选择性治疗 开发和结合两种治疗策略，即， 化疗的区域给药和生化调节 抗代谢作用。我们选择了一组 药代动力学特性应允许的抗代谢药 在现场保持较高的浓度 肿瘤在全身循环中，其生化反应 机制可能会有选择性地调节 与其他药物联合给药的细胞毒性。这些药物 它们是：5-溴-2‘-脱氧尿苷(BrdUrd)、5-碘-2’-脱氧尿苷 (IdUrd)、6-硫代鸟嘌呤(Tg)和6-巯基嘌呤(MP)-均为 核酸前体类似物，其中一个关键的靶向效应是 整合到DNA中。使用以下工具监控此目标参数 最近开发的灵敏分析技术应该会使 将培养细胞中的影响与相关的 活体内的动物和人体组织。要研究的变量 从细胞培养到临床的光谱影响 靶向掺入的选择性和细胞毒性包括(用于 每种药剂)：浓度、暴露时间、 以及用来影响水平的调节剂的效果 相关的细胞代谢物。人们感觉到，对 人类肿瘤类型特异性培养细胞(结肠--项目1A， 胶质瘤-项目1B)可能揭示共同的主题以及定义， 在某种程度上，与这些相关癌症相关的异质性 在活体内。从体外细胞推断的潜在能力 将在VX2兔身上探索体内培养环境 肿瘤模型(项目2)。此模型将用于定义 区域灌输在实现更高层次上的选择性优势 区域性和较低的系统性风险敞口以及 选择性改变模拟DNA的抗代谢调控 在肿瘤组织和正常宿主组织中的掺入。由此产生的 抗肿瘤效果和寄主毒性将根据 测量的类似物掺入组织DNA的选择性。 项目3评价地塞米松的药代动力学和毒性 以及作为一种手段的抗代谢调制的管理 将有趣的体外方案设计成合理的 临床研究。第一阶段/临床药理学研究(项目4) 涉及肝癌患者的肝动脉检查 化疗和抗代谢调节作为一种手段 将可能提高活性/选择性的方案从 将临床前模型引入临床进行相关、对照研究 时尚。项目5类似地延长了临床前的治疗方案 高级别胶质瘤患者的I-II期研究模型， 检查抗代谢药物治疗与 放射治疗(外照射和间质照射)。 预计本提案中采取的办法将导致 到临床前和临床前之间高效的双向交互 临床研究，至少验证了一些方法 选择并导致更具创造性、理性和强大的临床 利用这些抗代谢药物的治疗。

This proposal has as its objective the development of more selective therapy for hepatic tumors and high grade glimas by exploiting and combining two therapeutic strategies, namely, regional delivery of chemotherapy and biochemical modulation of antimetabolite action. We have selected for study a group of antimetabolites whose pharmacokinetics properties should permit the maintenance of a substanially higher concentration at the site of the tumor in the general circulation and, whose biochemical mechanisms invite potentially selective modulation of cytotoxicity by co-administration with other agents. These drugs are: 5-bromo-2'-deoxyuridine (BrdUrd), 5-iodo-2'-deoxyuridine (IdUrd), 6-thioguanine (TG) and 6-mercaptopurine (MP) - all nucleic acid precursor analogs where a crucial target effect is incorporation into DNA. Monitoring this target parameter with recently developed sensitive analytical techniques should make it feasible to correlate effects in cultured cells to those in relevant animal and human tissue in vivo. Variables to be studied across the spectrum from cell culture to the clinic as affecting the selectivity of target incorporation and cytotoxicity include (for each agent): influence of concentration, duration of exposure, and effects of modulating agents used to influence levels of relevant cellular metabolites. It is felt that examination of human tumor type specific cultured cells (colon-Project 1A, gliomas-Project 1B) may reveal common themes as well as define, to a degree, the heterogeneity relevant to these pertinent cancers in vivo. The potential ability to extrapolate from an in vitro cell culture to an in vivo setting will be explored in the VX2 rabbit tumor model (Project 2). This model will be used to define the selective advantage of regional infusions in achieving higher regional and lower systemic exposures as well as the ability of antimetabolite modulation to selectively change analog DNA incorporation in tumor versus normal host tissues. Resultant antitumor effect and host toxicity will be assessed relative to the selectivity of measured analog incorporation into tissue DNA. Project 3 evaluates the pharmacokinetics and toxicity of regional administration as well as of antimetabolite modulation as a means to and interesting in vitro regimens into rationally designed clinical studies. Phase 1/clinical pharmacology studies (Project 4) involving patients with hepatic cancers examine hepatic arterial chemotherapy and antimetabolite modulation as a means to extend regimens of potentially improved activity/selectivity from the preclinical models into the clinic in a relevant, controlled fashion. Project 5 similarly extends regimens from preclinical models into phase I-II studies in patients with high grade gliomas, examining the interaction of antimetabolite treatments with radiotherapy (both external beam and interstitial). It is anticipated that the approach taken in this proposal will lead to productive bidirectional interactions between preclinical and clinical investigation, validating at least some of the methods chosen and leading to more creative, rational, and potent clinical therapies utilizing these antimetabolites.