Abstract
After the discovery of the antiproliferative effects of cisplatin, the drug has developed into one of the most frequently used anticancer agents. Unfortunately, the use of cisplatin is hampered by severe side effects and by the resistance of several tumour types. These limitations have led to the development and evaluation
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of thousands of metal-containing compounds of which only a few have entered clinical trials. Nowadays, the platinum-containing complexes oxaliplatin and carboplatin have found important applications, whereas satraplatin is under consideration for approval. In addition, ruthenium complexes are regarded as promising alternatives for platinum complexes. Research to unravel the pharmacokinetics and pharmacodynamics of metal-based anticancer agents is required to understand the clinical behaviour of the drugs and to further optimise treatment regimens. Accurate and sensitive methods for the quantitative determination of metal-based anticancer agents are indispensable to study these aspects. Therefore, the introduction of inductively coupled plasma mass spectrometry (ICP-MS) in clinical pharmacological oncology research resulted in new opportunities in the field of quantitative analysis of metal-based anticancer agents. This technique has a high sensitivity and can be used to study heavy metals in a wide range of sample matrices. The aim of this thesis was to develop and validate analytical ICP-MS methods for the analysis of metal-based anticancer agents. Methods were developed to analyse platinum and ruthenium in biological fluids and to determine the amount of platinum bound to DNA. Furthermore, an assay was developed to assess environmental platinum contamination. These methods were applied to answer research questions concerning long-term pharmacokinetics, platinum-induced side effects, the effects of antidotes on platinum-induced side effects, and environmental monitoring. The use of the ultrasensitive ICP-MS applied in the current research has contributed to a better insight into long-term Pt pharmacokinetics, the effect of antidotes on the pharmacokinetics and -dynamics, and the level of environmental contamination. Furthermore, using ICP-MS, the investigation of pharmacokinetics and -dynamics is simplified because only a small sample volume is required. This decreases the inconvenience to the patients. The assays described in the current thesis have paved the way for further investigation of research questions concerning pharmacokinetics, mechanism of action, efficacy, and safety of metal-based anticancer agents. In addition to pharmacological applications, issues regarding environmental monitoring can be explored.
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