FACILITATING THE CLINICAL EVALUATION OF DENSPM

促进 DENSPM 的临床评估

• 批准号: 2458155
• 负责人: CARL W PORTER
• 金额: $ 14.68万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458155
• 关键词: analog; antineoplastics; athymic mouse; clinical trials; decarboxylases; drug screening /evaluation; enzyme activity; enzyme inhibitors; flow cytometry; high performance liquid chromatography; homeostasis; human subject; human therapy evaluation; melanoma; messenger RNA; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic growth; northern blottings; nuclear runoff assay; polyamines; southern blotting; spermine; tissue /cell culture

Two polyamine antagonists are scheduled for clinical trial here at RPCI-- one, a polyamine analog, N1 ,N11-diethylnorspermine (DENSPM), which deregulates polyamine homeostasis and potently inhibits tumor growth in preclinical model systems and the other, a polyamine inhibitor, CGP-48664, which target the polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase, depletes polyamine pools an inhibits tumor growth in vivo. Both agents have been rationally developed in two separate drug discover initiatives with the active involvement of this laboratory. Although not sequentially linked, the Specific Aims of this proposal are unified by the common goal of optimizing the clinical development of these promising new solid tumor therapies. In this context, the following activities are proposed: Aim 1, to validate the preclinically-indicated mode of action of both DENSPM and CGP-48664 in solid tumors obtained from patients treated with DENSPM or CGP48664; Aim 2, to examine the underlying regulatory mechanisms involved in the potent and heterogeneous induction of a polyamine catabolizing enzyme by DENSPM human melanoma cell lines--a response which appears from preclinical studies to be a critical in vivo determinant of antitumor activity of the analog; when technically possible findings ; Aim 3 to follow up on a recently observed association between distinct disturbances in polyamine homeostasis and the multidrug resistance phenotype in human melanoma cell lines--specifically, we will examine the basis for this apparent linkage and the therapeutic potential of polyamine antagonists in addressing multidrug resistance. Methodologies to be used in these studies include human cell culture techniques, biochemical enzyme assays, HPLC detection of polyamines and their analogs, rhodamine retention assays, flow cytometry Northern blots, Southern blots, nuclear run-on assays, mRNA half-life determinations and in vitro translation assays.

计划在RPCI上进行两名多胺拮抗剂进行临床试验 - 一个，一个多胺类似物，N1，N11-Diethylnorspermine（denspm），它 消除多胺稳态，并有效抑制肿瘤的生长 临床前模型系统，另一个是多胺抑制剂CGP-48664， 靶向多胺生物合成酶，s-腺苷甲氨酸 脱羧酶耗尽多胺池抑制体内肿瘤的生长。 两种药物都在两种单独的药物发现中合理发展 该实验室积极参与的举措。虽然不是 依次链接，该提案的具体目的由 优化这些有希望的新的临床发展的共同目标 实体瘤疗法。 在这种情况下，以下活动是 提议：目标1，以验证临床上指示的作用方式 从接受治疗的患者获得的实体瘤中的denSPM和CGP-48664 使用denSPM或CGP48664；目标2，检查基本的监管 涉及强大和异质诱导的机制 多胺通过denspm人黑色素瘤细胞系分解代谢酶 - a 从临床前研究中似乎是体内关键的反应 类似物的抗肿瘤活性的决定因素；在技​​术上可能 调查结果；目标3跟进最近观察到的最近的关联 多胺体内平衡和多剂量的明显干扰 人类黑色素瘤细胞系中的抗性表型 - 特别是我们将 检查这种明显联系和治疗潜力的基础 多胺拮抗剂在解决多药电阻方面。方法论 在这些研究中使用的是人类细胞培养技术， 生化酶测定，HPLC检测多胺及其类似物， 若丹明保留测定法，流式细胞术北印迹，南印迹， 核跑步测定，mRNA半衰期确定和体外 翻译测定。