SSAT AS A DETERMINANT OF DRUG ACTION
SSAT 作为药物作用的决定因素
基本信息
- 批准号:2896271
- 负责人:
- 金额:$ 28.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 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
项目摘要
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:诱导多胺分解代谢酶
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CARL W PORTER其他文献
CARL W PORTER的其他文献
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{{ truncateString('CARL W PORTER', 18)}}的其他基金
Antiproliferative Potential of Polyamine Catabolism
多胺分解代谢的抗增殖潜力
- 批准号:
6870266 - 财政年份:1998
- 资助金额:
$ 28.65万 - 项目类别:
Antiproliferative Potential of Polyamine Catabolism
多胺分解代谢的抗增殖潜力
- 批准号:
6614750 - 财政年份:1998
- 资助金额:
$ 28.65万 - 项目类别:
Antiproliferative Potential of Polyamine Catabolism
多胺分解代谢的抗增殖潜力
- 批准号:
7031629 - 财政年份:1998
- 资助金额:
$ 28.65万 - 项目类别:
Antiproliferative Potential of Polyamine Catabolism
多胺分解代谢的抗增殖潜力
- 批准号:
7214077 - 财政年份:1998
- 资助金额:
$ 28.65万 - 项目类别:
Antiproliferative Potential of Polyamine Catabolism
多胺分解代谢的抗增殖潜力
- 批准号:
6730529 - 财政年份:1998
- 资助金额:
$ 28.65万 - 项目类别:
FACILITATING THE CLINICAL EVALUATION OF DENSPM
促进 DENSPM 的临床评估
- 批准号:
2458155 - 财政年份:1995
- 资助金额:
$ 28.65万 - 项目类别:
FACILITATING THE CLINICAL EVALUATION OF DENSPM
促进 DENSPM 的临床评估
- 批准号:
2109135 - 财政年份:1995
- 资助金额:
$ 28.65万 - 项目类别:
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