Metal-based drugs remain a tiny minority of all drugs that are on the market. The success story of the quintessential metal-based drug cisplatin (CP), which is intravenously administered to 70% of all cancer patients, however, demonstrates the inherent potential of metal-based drugs. A distinct disadvantage of CP is the dose-limiting severe toxic-side effects that it exerts in patients. To better understand the biomolecular basis for its toxicity, we employed a metallomics method to observe all platinum metabolites that are formed in blood plasma. These investigations revealed that a highly toxic CP-derived hydrolysis product – the highly toxic monoaqua hydrolysis complex (MHC) – is formed within 5 min. More importantly, the application of this research tool has unraveled the mechanisms by which the chemoprotective agents sodium thiosulfate, d-methionine, N-acetyl-cysteine and l-glutathione modulate the metabolism of CP in plasma, namely by rapidly reacting with the MHC to form platinum‑sulfur complexes. Since CP remained in plasma for a considerable time, the possibility of ‘tuning’ its metabolism with chemoprotective agents in a desirable way has emerged. These observations are highly relevant because these chemoprotective agents were previously shown to significantly reduce the toxicity of CP in animal models, often without appreciably affecting its anticancer efficiency. Collectively, these results suggest that the toxicity of other metal-based drugs may be overcome if their metabolism in the bloodstream is adequately tuned with a suitable chemoprotective agent. This principle strategy has considerable potential in terms of harnessing the full potential of bringing more metal-based drugs to the market.

金属基药物在市场上所有药物中只占很小的一部分。典型的基于金属的药物顺铂（CP）的成功案例是对所有癌症患者中的70％进行静脉内给药，证明了基于金属的药物的内在潜力。CP的一个明显的缺点是它在患者中发挥剂量限制的严重的毒副作用。为了更好地了解其毒性的生物分子基础，我们采用了金属组学方法来观察血浆中形成的所有铂代谢物。这些调查表明，在5分钟内形成了高毒性CP衍生的水解产物-高毒性一水合水解复合物（MHC）。更重要的是，该研究工具的应用揭示了化学保护剂硫代硫酸钠，d-蛋氨酸，N-乙酰半胱氨酸和l谷胱甘肽调节血浆中CP的代谢，即通过与MHC快速反应形成铂硫复合物。由于CP在血浆中停留了相当长的时间，已经出现了以化学保护剂以理想的方式“调节”其代谢的可能性。这些观察结果高度相关，因为先前已证明这些化学保护剂可显着降低动物模型中CP的毒性，通常不会明显影响其抗癌效果。总的来说，这些结果表明，如果用合适的化学保护剂适当调节其在血液中的新陈代谢，则可以克服其他基于金属的药物的毒性。就充分利用将更多金属基药物推向市场的潜力而言，该主要策略具有巨大的潜力。