ANTIMETABOLITE SELECTIVITY--REGIONAL RX/MODULATION

抗代谢物选择性——区域 RX/调制

• 批准号: 3093966
• 负责人: WILLIAM D ENSMINGER
• 金额: $ 154.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3093966
• 关键词: antineoplastics; biomedical facility; drug metabolism; neoplasm /cancer chemotherapy

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.

这项建议的目标是发展更多的 选择性治疗肝肿瘤和高级别胶质瘤 利用并结合两种治疗策略，即， 局部化疗和生化调节 抗代谢作用 我们选择了一组 其药代动力学特性应允许 在现场保持相当高的浓度 肿瘤在全身循环中的分布， 机制邀请潜在的选择性调制， 通过与其他药剂共同施用来抑制细胞毒性。 这些药物 是：5-溴-2 '-脱氧尿苷（BrdUrd）、5-碘-2'-脱氧尿苷 （IdUrd）、6-硫鸟嘌呤（TG）和6-巯基嘌呤（MP）-所有 核酸前体类似物，其中关键的靶效应是 插入DNA。 监控此目标参数， 最近开发的敏感分析技术应该使它 将培养细胞中的效应与相关细胞中的效应相关联是可行的 动物和人体组织中。 要研究的变量 从细胞培养到临床， 靶掺入的选择性和细胞毒性包括（对于 每种试剂）：浓度的影响，暴露持续时间， 以及用于影响 相关的细胞代谢物。 有人认为，审查 人肿瘤类型特异性培养细胞（colon-Project 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，这些相关癌症的异质性 in vivo. 从体外细胞外推的潜在能力 将在VX 2家兔中探索体内环境的培养 肿瘤模型（项目2）。 该模型将用于定义 区域输液的选择性优势， 区域性和较低的系统性风险，以及 选择性改变类似物DNA的抗代谢物调节 与正常宿主组织相比， 所得 抗肿瘤作用和宿主毒性将相对于 测量的类似物掺入组织DNA的选择性。 项目3评价局部给药的药代动力学和毒性。 给药以及抗代谢物调节作为一种手段 有趣的体外治疗方案， 临床研究。 I期/临床药理学研究（项目4） 涉及肝癌患者检查肝动脉 化疗和抗代谢调节作为一种手段， 将潜在改善活性/选择性的方案从 临床前模型进入临床， 时尚. 项目5类似地将方案从临床前 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（外部射束和间质）。 预计本提案所采取的办法将导致 在临床前和 临床研究，验证至少部分方法 选择并导致更有创造性，理性和有效的临床 利用这些抗代谢物的疗法。