Detoxification of Electrophilic Chemical Threat Agents by Nucleophilic Scavengers

亲核清除剂对亲电化学威胁剂的解毒

基本信息

  • 批准号:
    7224542
  • 负责人:
  • 金额:
    $ 56.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-09-30 至 2011-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): One class of chemical threat agents for which medical countermeasures must be developed, the sulfur and nitrogen mustards (SNMs), exert their toxic effects through chemical reactions that involve an electrophilic intermediate. In this respect they are similar to many widely studied chemical carcinogens, and therefore strategies that have been used to detoxify these carcinogens should be applicable to the mustard agents. The primary strategies to be developed in this Project will block the ability of SNMs to form DNA adducts in exposed cells. We will use a combined in vitro/in vivo approach to determine the efficacy of two groups of potential protective agents: nucleophilic scavenging agents and agents that enhance endogenous conjugation reactions, particularly the addition of glutathione to the electrophile by the glutathione-S transferase (GST) enzymes. Two classes of nucleophilic scavenger will be tested: the dithiopurines (DTP) and ellagic acid. Both of these have been shown to completely detoxify the carcinogen BPDE. DTP has also been shown to detoxify melphalan, a nitrogen mustard, and in preliminary studies we have demonstrated facile reaction of DTP with a sulfur mustard, 2-chloroethyl ethyl sulfide. We will use cultured human cells derived from skin and lung to first test these protective compounds against SNMs, with cytotoxicity and mutagenesis as the primary endpoints. The most efficacious compounds will then be tested in two engineered human tissue models, one representing skin, the other representing airway epithelia, with toxic histopathology as the primary endpoint. Finally, the effective compounds will be tested in vivo in mice, using either topical treatment with subsequent analysis of skin, or intratracheal instillation with subsequent analysis of lung tissue. Toxicity endpoints in the mouse tissues will include histopathology (pyknotic/apoptotic nuclei, edema, vesication, infiltration, fibrosis) and induction of mutations in reporter genes carried in the transgenic mutation-reporter mice. These experiments will test the best scavenger, the best GSH/GST enhancer, and a combination of the two compounds. We will also test the sensitivity of human lymphocytes from 300 individuals to SNMs, and correlate the sensitivity with genotypes measured at several GST genetic loci that are polymorphic in the human population. Other biomarkers of exposure, including generalized protein adducts and a specific protein adduct will be analyzed where appropriate. Relevance: We expect to validate a strategy to efficiently detoxify electrophilic chemical threat agents, such as the SNMs and dimethyl sulfate. This will allow us to begin to formulate novel antidotes that could be used to protect personnel responding to an incident involving SNMs, and to stabilize exposed individuals against further damage. In addition, we will obtain data that indicates whether or not individuals with variants of a particular class of genes, the GSTs, are more susceptible to the effects of SNM toxicants.
描述(由申请人提供):必须开发医疗对策的一类化学威胁剂,硫和氮诱变剂(SNM),通过涉及亲电中间体的化学反应发挥其毒性作用。在这方面,它们与许多广泛研究的化学致癌物相似,因此用于解毒这些致癌物的策略应该适用于芥子气制剂。本项目中开发的主要策略将阻断SNM在暴露细胞中形成DNA加合物的能力。我们将使用体外/体内结合的方法来确定两组潜在保护剂的功效:亲核清除剂和增强内源性缀合反应的试剂,特别是通过谷胱甘肽-S转移酶(GST)将谷胱甘肽添加到亲电试剂中。将测试两类亲核清除剂:二硫嘌呤(DTP)和鞣花酸。这两种药物都被证明可以完全消除致癌物质BPDE的毒性。DTP也被证明可以解毒美法仑,一种氮芥,在初步研究中,我们已经证明了DTP与硫芥,2-氯乙基乙基硫醚的简单反应。我们将使用来自皮肤和肺的培养的人类细胞,首先测试这些保护性化合物对SNM的作用,细胞毒性和诱变作为主要终点。然后将在两个工程化人体组织模型中测试最有效的化合物,一个代表皮肤,另一个代表气道上皮,毒性组织病理学作为主要终点。最后,将在小鼠体内测试有效化合物,使用局部治疗和随后的皮肤分析,或使用肺内滴注和随后的肺组织分析。小鼠组织中的毒性终点将包括组织病理学(核固缩/凋亡、水肿、水疱、浸润、纤维化)和转基因突变报告基因小鼠中携带的报告基因突变的诱导。这些实验将测试最好的清除剂,最好的GSH/GST增强剂,以及两种化合物的组合。我们还将测试来自300个个体的人淋巴细胞对SNMs的敏感性,并将敏感性与在人群中多态的几个GST基因位点测量的基因型相关联。适当时,将分析其他暴露生物标志物,包括广义蛋白加合物和特定蛋白加合物。相关性:我们希望验证一种有效地解毒亲电化学威胁剂(如SNM和硫酸二甲酯)的策略。这将使我们能够开始制定新的解毒剂,可用于保护应对涉及SNM事件的人员,并稳定受影响的个人,使其免受进一步损害。此外,我们将获得数据,表明是否与特定类别的基因,GST的变异的个人,更容易受到SNM毒物的影响。

项目成果

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科研奖励数量(0)
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Michael C MacLeod其他文献

Michael C MacLeod的其他文献

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{{ truncateString('Michael C MacLeod', 18)}}的其他基金

Mechanisms of ATF3-induced mammary tumorigenesis
ATF3诱导乳腺肿瘤发生的机制
  • 批准号:
    7738885
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Detoxification of Electrophilic Chemical Threat Agents by Nucleophilic Scavengers
亲核清除剂对亲电化学威胁剂的解毒
  • 批准号:
    7665443
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Mechanisms of ATF3-induced mammary tumorigenesis
ATF3诱导乳腺肿瘤发生的机制
  • 批准号:
    7210219
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Mechanisms of ATF3-induced mammary tumorigenesis
ATF3诱导乳腺肿瘤发生的机制
  • 批准号:
    7996640
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Detoxification of Electrophilic Chemical Threat Agents by Nucleophilic Scavengers
亲核清除剂对亲电化学威胁剂的解毒
  • 批准号:
    7294242
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Detoxification of Electrophilic Chemical Threat Agents by Nucleophilic Scavengers
亲核清除剂对亲电化学威胁剂的解毒
  • 批准号:
    7906825
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Mechanisms of ATF3-induced mammary tumorigenesis
ATF3诱导乳腺肿瘤发生的机制
  • 批准号:
    7534043
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Mechanisms of ATF3-induced mammary tumorigenesis
ATF3诱导乳腺肿瘤发生的机制
  • 批准号:
    7325780
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Detoxification of Electrophilic Chemical Threat Agents by Nucleophilic Scavengers
亲核清除剂对亲电化学威胁剂的解毒
  • 批准号:
    7473988
  • 财政年份:
    2006
  • 资助金额:
    $ 56.25万
  • 项目类别:
Construction of gene expression signatures with RAGE
使用 RAGE 构建基因表达特征
  • 批准号:
    6585975
  • 财政年份:
    2002
  • 资助金额:
    $ 56.25万
  • 项目类别:

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