报告主题： What do we really know about the mechanism of action of platinum drugs 报 告 人： Dan Gibson 职 务： 职 称： 工作单位： 以色列希伯来大学 报告时间： 2014年4月17日 报告地点： 生化学院会议室 参加人数： 主办单位： 生物与化学工程学院 报告简介：

讲座摘要：

What do we really know about the mechanism of action of platinum anticancer agents?

Since the discovery of the anticancer activity of cisplatin in the 1960s, researchers have been trying to elucidate the mechanism of action of platinum anticancer agents. It is widely accepted today that it is the binding of the Pt moiety to nuclear DNA that triggers a cascade of cellular responses that in many cases leads to the death of the cancer cell. It is also believed that only about 1% of the cellular platinum is bound to the nuclear DNA. So what happens to the rest of the cellular platinum?

Unfortunately it is not possible to monitor the fate of Pt drugs inside cancer cells since there are no analytical technologies capable of characterizing Pt complexes at nM levels in biological solutions. Our approach was to use aqueous extracts of cancer cells as a model for the cytoplasm and to try to follow the fate of ¹⁵N and ¹³C labelled Pt complexes by two dimensional NMR spectroscopy.

Glutathione that is present in mM concentrations in cells is believed to bind to most of the cellular platinum preventing it from binding to nuclear DNA. We found out that contrary to common belief it seems that glutathione may not be the major cellular target of cisplatin. We also note that the GSH levels do not affect the levels of platinum binding to nuclear DNA.

Pt(IV) complexes are believed to be very inert to substitution and hydrolysis and are believed to be activated inside the cells by reduction (by GSH and ascorbate) losing the two axial ligands and releasing the cytotoxic Pt(II) agent. We also looked at the reduction of Pt(IV) pro-drugs by cancer cell extracts and observed that GSH and ascorbate are not the major reducing agents of Pt(IV) pro-drugs in cells. In addition we will report on some unexpected chemistry of Pt(IV) complexes in the context of design of novel Pt(IV) pro-drugs.