SSAT AS A DETERMINANT OF DRUG ACTION

SSAT 作为药物作用的决定因素

• 批准号: 6173381
• 负责人: CARL W PORTER
• 金额: $ 29.51万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173381
• 关键词: acyltransferase; antineoplastics; carcinogenesis; cell line; cytotoxicity; disease /disorder model; enzyme activity; enzyme induction /repression; gene expression; gene targeting; genetic translation; genetically modified animals; homeostasis; laboratory mouse; melanoma; messenger RNA; neoplastic cell; pharmacokinetics; phorbols; protein kinase C; spermidine; spermine

DESCRIPTION: Induction of the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) by certain polyamine analogs represents one of the most potent known gene responses attributable to an anticancer drug. The relationship of this response to antitumor activity and host toxicities has not yet been clearly established. The proposed studies build on the following observations and developments involving this novel enzyme: a) a polyamine analog currently undergoing phase 1 clinical trial (N1, N11 -diethyl-norspermine (DENSPM) is an extremely potent inducer of this enzyme; b) melanoma cells are more responsive to SSAT induction than most other tumor cell types; c) biological correlations suggest a causal linkage between analog induction of SSAT activity and in vitro and in vivo growth sensitivity of tumor cells; d) overexpression of the enzyme in transgenic animals causes striking phenotypic changes involving skin and the female reproductive tract; e) strong similarities between SSAT transgenic animals and certain other transgenics suggest a role for the enzyme in tumor promotion and f) SSAT gene expression in mouse skin and melanoma cells is markedly increased by 12-O-tetradecanoyl-13-phorbol acetate (TPA). The Specific Aims propose: 1) to examine the cellular consequences of SSAT induction in human melanoma cells transfected with a tetracycline-inducible SSAT expression system; 2) to investigate the significance of translational control of SSAT gene expression; 3) to examine the physiological role of SSAT in tissue function using activated gene knock-out (via subcontract agreement with Dr. J. Janne's group Kuopio, Finland); 4) to utilize systems developed in aims 1-3 to study the role of SSAT in determining antitumor and toxicity responses to clinically relevant polyamine antagonists; 5) to determine via cross-breeding experiments whether SSAT overexpression renders animals more or less prone to skin carcinogenesis and 6) as a mechanistic correlate to aim 5, they propose to examine the effects of tumor promters on SSAT gene expression and the possible role of protein kinase C as a mediator of SSAT induction by both TPA and the polyamine analogs. In addition to investigating the biological significance of this unusual enzyme response, the proposed studies are designed to provide therapeutic insights and preclinical model systems for use in facilitating the ongoing clinical and preclinical development of experimental anticancer therapies targeting polyamines.

描述：多胺分解代谢酶的诱导 某些多胺类似物产生的亚精胺/精胺 N1-乙酰转移酶 (SSAT) 代表了已知最有效的基因反应之一 抗癌药。 这种反应与抗肿瘤活性的关系 和宿主毒性尚未明确确定。 拟议的 研究建立在以下涉及此的观察和进展的基础上 新型酶：a) 一种多胺类似物，目前正在进行 1 期临床 试验（N1，N11-二乙基去甲精胺（DENSPM）是一种极其有效的诱导剂 这种酶； b) 黑色素瘤细胞对 SSAT 诱导的反应比 大多数其他肿瘤细胞类型； c) 生物相关性表明因果关系 SSAT 活性的模拟诱导与体外和体内之间的联系 肿瘤细胞的生长敏感性； d) 酶的过度表达 转基因动物引起皮肤和皮肤的显着表型变化 女性生殖道； e) SSAT 转基因之间的强烈相似性 动物和某些其他转基因表明该酶在肿瘤中发挥作用 f) SSAT 基因在小鼠皮肤和黑色素瘤细胞中的表达 12-O-十四烷酰基-13-佛波醇乙酸酯 (TPA) 显着增加。 这 具体目标建议：1) 检查 SSAT 的细胞后果 用四环素诱导剂转染的人黑色素瘤细胞中的诱导 SSAT表达系统； 2）研究翻译的意义 控制SSAT基因表达； 3）检验生理作用 使用激活基因敲除的组织功能 SSAT（通过分包 与 J. Janne 博士的团队（芬兰库奥皮奥）达成协议）； 4）利用系统 目标 1-3 中开发的目的是研究 SSAT 在确定抗肿瘤和 对临床相关多胺拮抗剂的毒性反应； 5）到 通过杂交实验确定 SSAT 过度表达是否会导致 动物或多或少容易发生皮肤癌，6) 作为一种机制 与目标 5 相关，他们建议检查肿瘤启动子对 SSAT 基因表达和蛋白激酶 C 作为介质的可能作用 TPA 和多胺类似物诱导 SSAT 的过程。 此外 研究这种不寻常的酶反应的生物学意义， 拟议的研究旨在提供治疗见解和 用于促进正在进行的临床和 实验性抗癌疗法的临床前开发 多胺。