XAS STUDIES OF METAL AND METALLOID-CONTAINING CHEMOTHERAPY AGENTS

Stanford University, Stanford CA

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Abstract

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[unreadable] (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.