POLYAMINE ANALOG AND INHIBITOR REGULATION OF CELL CYCLE

细胞周期的多胺类似物和抑制剂调节

• 批准号: 6375597
• 负责人: CARL W PORTER
• 金额: $ 29.39万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375597
• 关键词: analog; antineoplastics; apoptosis; athymic mouse; cell cycle; cell growth regulation; cell proliferation; complementary DNA; decarboxylase inhibitor; drug design /synthesis /production; drug metabolism; human tissue; melanoma; molecular genetics; mutant; neoplasm /cancer pharmacology; neoplastic cell; oncoprotein p21; p53 gene /protein; pharmacogenetics; pharmacokinetics; polyamines; protein structure function; spermidine; tissue /cell culture

The therapeutic potential of cell cycle regulatory discoveries is just being realized and while they provide clear opportunity for the development of new and novel anticancer agents, their more immediate potential resides in improving the use of existing drugs. DNA-damaging agents are an obvious example of drugs being investigated from this perspective. On the basis of recent findings, we believe that two polyamine antagonists developed with the active involvement of this laboratory and currently undergoing clinical evaluation, have previously unrealized potential as modulators of cell cycle regulatory pathways. This belief is predicated on our recent observation that the polyamine analog N1, N11-diethylnorspermine (DENSPM) and the polyamine enzyme inhibitor CGP-48664 potently activate the p53, p21, Rb pathway and induce G1 cell cycle arrest in MALME-3M human melanoma cells containing wild- type p53. In SK-MEL-28 melanoma cells containing mutated p53, DENSPM induces a rapid and massive apoptotic response. The findings represent the first linkage between polyamines and the cell cycle regulatory machinery. The proposed studies will investigate the therapeutic and biological significance of these findings in human melanoma cell lines. This disease-focus is based on relative high sensitivity of melanoma to these agents in preclinical systems; the targeting of melanoma in Phase II clinical trials and the fact that melanoma tends to differ from other solid tumors with respect to p53 expression levels and mutation frequency. Thus, the following Specific Aims propose: (1) to examine the cell cycle regulatory pathways responsible for polyamine analog and inhibitor induction of G1 arrest in MALME-3M melanoma cells, focusing initially on the contribution of p53 and p21; (2) to identify the effectors responsible for polyamine analog induction of apoptosis in SK-MEL- 28 cells; (3) to investigate the polyamine-related initiating event(s) responsible for analog- and inhibitor-induced growth arrest and apoptosis; and (4) to confirm that specific analog- and inhibitor-induced effects that occur in vitro also occur in vivo. It is our belief that an understanding of cell cycle regulatory events by the two polyamine antagonists will contribute rationally to their deployment as anticancer agents and/or chemopreventive agents and at the same time, provide new insights into how the well-recognized polyamine requirement for cell growth interfaces with the complex pathways that control cell cycle progression and apoptosis.

细胞周期调控发现的治疗潜力刚刚被认识到，虽然它们为开发新型抗癌药物提供了明显的机会，但它们更直接的潜力在于改善现有药物的使用。 DNA 损伤剂是从这个角度研究药物的一个明显例子。根据最近的研究结果，我们相信在该实验室的积极参与下开发的两种多胺拮抗剂目前正在进行临床评估，它们具有以前未实现的作为细胞周期调节途径调节剂的潜力。这一信念基于我们最近的观察，即多胺类似物 N1、N11-二乙基去甲精胺 (DENSPM) 和多胺酶抑制剂 CGP-48664 有效激活 p53、p21、Rb 通路，并诱导含有野生型 p53 的 MALME-3M 人黑色素瘤细胞中的 G1 细胞周期停滞。在含有突变 p53 的 SK-MEL-28 黑色素瘤细胞中，DENSPM 诱导快速且大量的细胞凋亡反应。这些发现代表了多胺和细胞周期调节机制之间的第一个联系。 拟议的研究将调查这些发现在人类黑色素瘤细胞系中的治疗和生物学意义。这种疾病焦点是基于黑色素瘤在临床前系统中对这些药物的相对较高的敏感性； II 期临床试验中针对黑色素瘤的研究，以及黑色素瘤在 p53 表达水平和突变频率方面往往与其他实体瘤不同的事实。 因此，提出以下具体目标：（1）检查负责多胺类似物和抑制剂诱导 MALME-3M 黑色素瘤细胞中 G1 期停滞的细胞周期调节途径，首先关注 p53 和 p21 的贡献； (2)鉴定负责多胺类似物诱导SK-MEL-28细胞凋亡的效应子； (3) 研究导致类似物和抑制剂诱导的生长停滞和细胞凋亡的多胺相关起始事件； (4) 确认体外发生的特定类似物和抑制剂诱导的效应也在体内发生。我们相信，对两种多胺拮抗剂的细胞周期调节事件的了解将有助于它们作为抗癌剂和/或化学预防剂的合理部署，同时，为细胞生长所需的多胺与控制细胞周期进展和细胞凋亡的复杂途径如何相互作用提供新的见解。