Since the appearance of the first paper on cis-diamminedichloroplatinum(II), abbreviated cisplatin, and cisplatin's early successes in the treatment of a variety of tumors, the topics of metal-DNA binding and platinum-antitumor chemistry have enjoyed a fair amount of interest from chemists, pharmacologists, biochemists, biologists, and medical researchers. In fact, cisplatin, together with carboplatin and oxaliplatin, enjoy the status of the world's best-selling anticancer drugs. As a result, many multidisciplinary studies have been conducted, and detailed knowledge of the mechanism of cisplatin and related drugs is now available. Moreover, this knowledge has clearly resulted in much-improved clinical administration protocols and research on and application of other, related drugs containing transition metals.
Like cisplatin, all chemotherapeutic drugs have drawbacks, including intrinsic or acquired resistance and toxicity. Efforts to reduce these side effects have inspired chemists to synthesize a variety of analogues, but only a small number of new drugs have been found to be acceptable for clinical application. During the last two decades, the efforts of many research groups have led to improved understanding of cisplatin's mechanism of action and more rational design of new platinum drugs. Nevertheless, many mechanistic questions remain, especially for the drugs containing nonplatinum metals and for the newer derivatives of cisplatin.
The main objective of our researchis to increase understanding of the design and mechanisms of action of antitumor metallodrugs and to use this enhanced knowledge to develop new classes of metallodrugs that have truly novel mechanisms of action and novel spectra of biomedical activity. Our secondary objectives are to (1) design and study transition metal-based agents that circumvent known clinical drawbacks of "conventional" cisplatin (resistance, limited spectrum of activity, lack of specificity) through different molecular-level actions and through molecular and cellular targeting and (2) enhance our knowledge of the molecular and macromolecular effects of existing clinical agents and use this knowledge to underpin the process of designing new metallodrugs.
First we examine novel modes of modification of DNA and proteins by new platinum coordination compounds as potential antitumor drugs, in particular DNA modifications (including their recognition and repair) of various new antitumor analogues of platinum complexes to better understand the factors contributing to their biological activity. Efforts have also been directed at designing transition-metal antitumor agents other than platinum. In the design of these new drugs, ruthenium complexes have attracted much interest as well. We perform comparative studies on naked nucleic acids, DNA in nucleosomes, and DNA isolated from cells treated with metal-based agents. We investigate the correlation between DNA binding modes (including resulting conformational distortions, their recognition by DNA-binding proteins and repair) and antitumor efficacy of novel metal-based compounds. It is generally accepted that the anticancer activity of platinum coordination complexes arises from their ability to damage DNA—the adducts formed being various types of cross-links. Hence, the overall significance of our research is to continue to test the working hypothesis that metal-based drugs, which bind to cellular targets in a manner fundamentally different from that of conventional cisplatin and its analogues used in the clinic, have altered biological properties including the spectrum and intensity of antitumor activity.
Another aim is to investigate the molecular mechanisms underlying the biological effects of platinum and ruthenium prodrugs that can be photoactivated with visible laser light and have novel modes of interaction with DNA and proteins. Anticancer treatments that use site-selective, photoinduced cytotoxicity have the potential to eliminate the unwanted side effects of conventional chemotherapy by avoiding damage to healthy cells. Photoactivation may also allow new, and more toxic, reaction pathways to be accessed. Photodynamic therapy (PDT), which involves using drugs (usually porphyrins or related molecules) that absorb light and subsequently react with cellular components to produce cytotoxic species, has received the most attention to date. Photofrin, the most widely used drug of this type, is an ill-defined mixture of up to 60 different substances and remains in the body for six to eight weeks, resulting in prolonged skin sensitivity. It requires oxygen for its mechanism of toxicity in PDT, although tumors often have a poor oxygen supply. Therefore, there is a need for alternative photoactive drugs. Metal-based photoactivated anticancer drugs might offer significant advantages over porphyrin-based phototherapies. Importantly, the mechanism of photoreactivity of metal-based photoactivated anticancer drugs is independent of oxygen. These complexes, therefore, have the potential to combine both photoinduced cell death and fluorescence imaging of the location and efficiency of the photoactivation process.
A third aim is to determine the pharmacologic factors responsible for antitumor effects of new platinum complexes containing biologically active carrier ligands. Ligands are selected that may serve as molecular carriers to obtain a specific delivery of the antitumor drug to and its accumulation in target tumor cells (drug targeting and delivery) or synergistic pharmacologic activities.
We also study the effect of DNA adducts of novel antitumor platinum and ruthenium complexes and resulting new structural motifs in DNA on DNA-binding properties of transcription factors, zinc-finger proteins, and protein components of repair systems. An important feature of these DNA-binding proteins is that they affect processes leading to programmed cell death or necrosis—that is, processes that play a critical role in the mechanism of several antitumor metal-based drugs. Given that DNA adducts of antitumor metal-based drugs may trigger apoptosis or necrosis in cells sensitive to these agents, compounds that lower the affinity of these DNA-binding proteins to DNA may be more effective in inducing apoptosis or necrosis, which may promote the antitumor effects of these compounds.
Another interest is the role of metallothioneins (MTs), a class of cysteine-rich metalloproteins involved in heavy metal detoxification, in the mechanisms underlying antitumor effects of platinum and ruthenium compounds. The direct interaction of MT with cisplatin is believed to be the primary cause of the tumor-cell resistance. Therefore, the following questions are addressed: whether MTs are involved in the demetallation of DNA modified by antitumor osmium, platinum, or ruthenium drugs; whether there are differences in their interaction with metallated DNA modified by cisplatin versus novel antitumor osmium, platinum, or ruthenium complexes; and whether platinum (ruthenium)-containing MTs can serve as a drug reservoir for DNA metallation.
We are trying to determine the significance of several pharmacologic factors that may play a role in the mechanism of biological effects of metallodrugs at moderately elevated temperatures—namely, alterations in the target DNA modification and cellular processing of these modifications and their cellular uptake. Chemotherapy combined with elevated temperature (hyperthermia) represents an interesting approach in the treatment of cancer compared with chemotherapy alone. Broadening the possibilities to exploit platinum antitumor drugs in combination with hyperthermia in the clinic depends on understanding the mechanism of the combined effect of existing platinum agents and hyperthermia, with a view toward developing new modes of treatment. Therefore, it is also of great interest to understand details of the molecular and biochemical mechanisms underlying the biological efficacy of cisplatin at elevated temperatures.
The results of these studies will have important implications for the anticancer effectiveness of new platinum and ruthenium complexes in clinical practice. We propose new concepts for mechanisms underlying anticancer effects of platinum and ruthenium compounds, including new structure–pharmacologic relationships of platinum and ruthenium compounds.
Last updated September 2009