XAS STUDIES OF METAL AND METALLOID-CONTAINING CHEMOTHERAPY AGENTS

金属和类金属化疗剂的 XAS 研究

• 批准号: 7598131
• 负责人: CHRISTIAN J DOONAN
• 金额: $ 0.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7598131
• 关键词: Acute; Acute Promyelocytic Leukemia; Arsenic; Arsenic Trioxide; Arsenicals; Binding; Biological; Chemicals; Chemistry; Chemistry, Other; Chronic; Clinical Research; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Drug Design; Elements; Funding; Grant; Institution; Knowledge; Malignant Neoplasms; Mammalian Cell; Medical; Metals; Molecular; Nature; Organism; Personal Satisfaction; Physiological; Poison; Research; Research Personnel; Resources; Source; Spectrum Analysis; Staging; Therapeutic; Toxic effect; Trixenox; United States National Institutes of Health; absorption; chemotherapeutic agent; chemotherapy; improved; in vivo; middle age; response; titanocene dichloride

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The presence of metals and metalloids in the biosphere can be innocuous, beneficial or deleterious to living systems. A determining factor of the therapeutic or toxic nature is the chemical form and valence state of the particular element. Although the relationship between chemical form and toxicity or beneficial effects is well established in many cases, the underlying in vivo mechanisms often remain unclear. In the medical field, the use of metals and metalloids as chemotherapeutic agents is increasing, consequently, a more comprehensive understanding of their intracellular molecular interactions is clinically vital. This is particularly true for the chemopharmaceutical Trisenox¿ (arsenic trioxide). Arsenic has been utilized as an acute poison since the middle ages, moreover, it is known that at chronic exposure levels arsenic compounds are carcinogenic. In contrast, recent clinical studies demonstrated that arsenic trioxide is a highly effective treatment for acute promyelocytic leukemia. It is intriguing that this chemically simple compound can both cause and effectively treat a biologically complex disease such as cancer. However, the molecular mechanisms that engender these paradoxical biological responses are not understood. A detailed knowledge of the physiological chemistry of arsenicals is essential, as the absence of a cellular mechanism will impede the development of improved chemopharmacueticals. Furthermore, the intracellular chemistry of other trial stage and potential chemotherapeutic agents, such as titanocene dichloride are also poorly understood, thus impeding advances in drug design. We propose to use x-ray absorption spectroscopy (XAS) to directly study the chemical forms of potential and chemotherapeutic metal and metalloid compounds in cultured mammalian cells. This study should assist in understanding the molecular mechanisms underlying toxicity.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 生物圈中金属和金属的存在可能是无害的，有益的或有害的。治疗性或有毒性质的决定性因素是特定元素的化学形式和价状态。尽管在许多情况下，化学形式与毒性或有益作用之间的关系已经很好地确定，但基本的体内机制通常仍不清楚。在医学领域，将金属和金属固醇用作化学治疗剂的使用正在增加，因此，对其细胞内分子相互作用的更全面了解在临床上至关重要。对于化学药物三氧化物（三氧化物）而言，尤其如此。此外，砷从中世纪起就被用作急性毒药，而且众所周知，在慢性暴露水平下，砷化合物具有致癌性。相反，最近的临床研究表明，三氧化砷是对急性临床前白血病的高效治疗方法。有趣的是，这种化学简单的化合物既可以引起并有效地治疗诸如癌症之类的生物学复杂疾病。但是，尚不清楚产生这些自相矛盾的生物学反应的分子机制。对砷的物理化学的详细知识至关重要，因为缺乏细胞机制会阻碍改善化学药物的发展。此外，其他试验阶段的细胞内化学和潜在的化学治疗剂（例如二氯化钛二氯化）也被鲜为人知，从而阻碍了药物设计的进步。我们建议使用X射线抽象光谱（XAS）直接研究培养的哺乳动物细胞中潜在的和化学治疗金属和金属化合物的化学形式。这项研究应有助于理解毒性的分子机制。