XAS STUDIES OF METAL AND METALLOID-CONTAINING CHEMOTHERAPY AGENTS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 生物圈中金属和类金属的存在对生物系统可能是无害的、有益的或有害的。决定治疗或毒性性质的一个因素是特定元素的化学形式和价态。尽管在许多情况下，化学形式与毒性或有益效果之间的关系已经很好地建立了，但潜在的体内机制往往仍不清楚。在医学领域，金属和类金属作为化疗药物的使用越来越多，因此，更全面地了解它们在细胞内的分子相互作用具有重要的临床意义。对于化学药物三氧化二砷来说，情况尤其如此。自中世纪以来，砷一直被用作一种急性毒物，而且，人们知道，在长期接触水平下，砷化合物是致癌的。相比之下，最近的临床研究表明，三氧化二砷是一种治疗急性早幼粒细胞白血病的高效药物。耐人寻味的是，这种化学上简单的化合物既可以引发癌症，也可以有效地治疗癌症等生物复杂疾病。然而，产生这些自相矛盾的生物反应的分子机制尚不清楚。对砷化合物的生理化学有详细的了解是必要的，因为缺乏细胞机制将阻碍改进的化学药物的开发。此外，其他试验阶段和潜在的化疗药物，如二氯二茂钛的细胞内化学也知之甚少，因此阻碍了药物设计的进展。我们建议使用X射线吸收光谱(XAS)来直接研究培养的哺乳动物细胞中潜在的和具有化学治疗作用的金属和类金属化合物的化学形态。这项研究将有助于理解潜在毒性的分子机制。

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.