The binding of antitumor metal complexes toward proteins

Platinum-based drugs are utilized in more than 50% of treatments in cancer chemotherapy resulting in a total turn- over of more than 2 billion US dollars per year. Only a small portion of thousands of synthesized platinum compounds have entered clinical trials, and only six platinum-based drugs have been approved worldwide or in a single country. Cancer is one of the diseases causing many deaths in industrialized world. For example, in 2003 in Austria 19.231 people died from cancer - 25% of all cases of death - and every 4th case of death of men and every 5th of women was due to cancer. The development of a new drug compound takes usually 10 to 15 years and costs ca. one billion USD. The challenge for accelerating the drug discovery and development procedure and reducing costs of launching new, more efficient and less toxic drugs is to develop early stage forecasting methods about the expectable efficiency of new drugs. Modern analytical techniques offer the opportunities to study the interactions with biological targets in the blood stream and the cell and give more precise information on processes occurring in these tissues. Mass spectrometric research characterizing the protein binding of established drugs and promising drug candidates could lead to a characteristic pattern for the interaction of more or less active metal-based drugs to proteins. The most important compounds out of established and promising tumor-inhibiting platinum and ruthenium metal complexes will be chosen and characterized in terms of binding stoichiometry, kinetics and preferential binding to amino acids, peptides and proteins as well as the corresponding adducts` stability will be determined. For novel metal complexes, the proposed screening could support the choice of compounds for further development. In our opinion fast and reliable screening by mass spectrometry could take a leading role in further metallodrug-protein binding investigations. The development of such an analysis method in combination with cell biology studies could then be used as simple and rapid drug assay with eventually good predictivity of the antitumor potential at an early development stage.