SSAT AS A DETERMINANT OF DRUG ACTION

SSAT 作为药物作用的决定因素

• 批准号: 2896271
• 负责人: CARL W PORTER
• 金额: $ 28.65万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 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/2896271
• 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 某些多胺类似物对亚精胺/精胺N1-乙酰转移酶(SSAT)的影响 代表了已知的最有效的基因反应之一，可归因于 抗癌药物。这种反应与抗肿瘤活性的关系 寄主毒性尚未明确确定。建议数 研究建立在以下观察和涉及到的发展的基础上 新酶：a)一种多胺类似物，目前正处于临床1期 试验(N1，N11-二乙基去甲精胺(DENSPM)是一种非常有效的诱导剂 B)黑色素瘤细胞对SSAT诱导的反应比 大多数其他类型的肿瘤细胞；c)生物相关性提示原因 模拟诱导SSAT活性与体内外的联系 肿瘤细胞的生长敏感性；d)该酶在 转基因动物引起显著的表型变化，涉及皮肤和 女性生殖道；e)SSAT转基因基因之间有很强的相似性 动物和其他转基因研究表明，这种酶在肿瘤中发挥了作用 SSAT基因在小鼠皮肤和黑色素瘤细胞中的表达 12-O-十四酰-13-佛波醇醋酸酯(TPA)显著增加。这个 具体目标建议：1)检查SSAT的细胞后果 四环素诱导物对人黑色素瘤细胞的诱导作用 SSAT表达系统；2)研究翻译的意义 SSAT基因表达的调控；3)检测SSAT的生理作用 利用激活基因敲除的组织功能中的SSAT(通过转包 与J.Janne博士的团队达成协议(芬兰库奥皮奥)；4)利用系统 在AIMS 1-3中开发，用于研究SSAT在确定抗肿瘤和 临床相关多胺拮抗剂的毒性反应；5) 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，这是一种 与目标5相关，他们建议检查肿瘤促进剂对 SSAT基因表达与蛋白激酶C的可能介导性作用 TPA和多胺类似物对SSAT的诱导作用。除了……之外 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洞察力和 临床前模型系统，用于促进正在进行的临床和 实验性抗癌靶向治疗的临床前研究进展 多胺。