XAS STUDIES OF METAL AND METALLOID-CONTAINING CHEMOTHERAPY AGENTS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 生物圈中金属和类金属的存在可能对生命系统无害，有益或有害。治疗或毒性性质的决定因素是特定元素的化学形式和价态。虽然在许多情况下，化学形式与毒性或有益作用之间的关系已经很好地建立起来，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，更全面地了解它们的细胞内分子相互作用在临床上是至关重要的。这对于化学药物Trisenox（三氧化二砷）来说尤其如此。自中世纪以来，砷一直被用作急性毒药，此外，众所周知，长期接触砷化合物是致癌的。相反，最近的临床研究表明，三氧化二砷是一种非常有效的治疗急性早幼粒细胞白血病。有趣的是，这种化学上简单的化合物既能引起又能有效治疗生物学上复杂的疾病，如癌症。然而，产生这些矛盾的生物反应的分子机制还不清楚。砷的生理化学的详细知识是必不可少的，因为缺乏细胞机制将阻碍改进化学药物的发展。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，从而阻碍了药物设计的进展。我们建议使用X-射线吸收光谱（XAS）直接研究潜在的化学形式和化学治疗的金属和类金属化合物在培养的哺乳动物细胞。这项研究应有助于了解潜在的毒性的分子机制。

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.