Interactions of antitumor metallodrugs with serum proteins: advances in characterization using modern analytical methodology.

The mortality rates from various tumor types can be reduced dramatically by use of highly active drugs. This is particularly true for platinum-based drugs, being among the most effective antineoplastic agents for a number of malignancies (e.g., testicular, ovarian, head and neck, and bladder cancers). Platinum coordination compounds have been successfully applied in cancer chemotherapy for more than 25 years since the introduction of the parent compound for this class of antitumor agents, namely, cis-[diamminedichloroplatinum(II)] (1) known as cisplatin1 (for structural formula, see Figure 1). Over these decades, a great deal of effort has been devoted to synthesis and testing of the tumor-inhibiting profiles for new metal complexes, with the major impetus toward development and implementation of novel anticancer drugs. These are anticipated to have superior efficacy, increased selectivity for tumor tissue, reduced toxicity, a wider spectrum of activity, lack of tumor cell resistance, and improved pharmacological characteristics (e.g., possibility of oral administration) as compared to cisplatin. Still, of thousands of tested compounds, only a fraction (about 30) have entered clinical trials and merely three Pt drugs have eventually been approved worldwide.2,3 Part of the reasons for low productivity of anticancer metallodrug discovery and development is a limited knowledge about the mode, in which metabolic state the metal complex penetrates the tumor cell and how much is inactivated. In view of the fact that a vast majority of cytotoxic metal-containing compounds are administered intravenously, special consideration should therefore be given to interactions of the metal drug with macromolecular blood components, which can then be taken up by and accumulate in tumor tissue. In this context, binding toward serum proteins that may perform a transport function for a platinum (or other) metal, for example, albumin or transferrin, appears to be the most important issue, because such interactions determine also the overall drug distribution and excretion and differences in efficacy, activity, and toxicity.4,5 As follows from the first review paper by Kratz,4 early work on studying interactions of antitumor metal complexes with plasma components, mostly carrier proteins, has been conventionally performed using various spectroscopic techniques, including electronic, vibrational, circular dichroism (CD), fluorescence, and NMR spectroscopy. Although providing valuable information on the nature and number of protein active sites participating in binding, as well as on its rate, specificity, and reversibility, these techniques require the separation of excess metal from its protein-bound form (typically achieved by ultrafiltration, dialysis, or gel filtration6), which makes the whole procedure laborious, time-consuming, and possibly entailing a certain loss of binding. The further inadequacy * To whom correspondence should be addressed. Telephone: +43-1-427752600.Fax: +43-1-4277-9526.E-mailaddresses: [email protected]; [email protected]. † Permanent address: Saratov Institute of Radiation, Chemical and Biological Warfare Defense, 410037 Saratov, Russia.