New Platinum Drugs

Despite the synthesis of many hundreds of cisplatin analogues over the past 20 years, there have been relatively few leads to the discovery of novel platinum drugs capable of circumventing tumour resistance to cisplatin/carboplatin. 

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In the search for a more successful drug, numerous alternative concepts in the design of new platinum drugs emerged. Requirements that have influenced the search for new complexes include reduction in toxicity, increased spectrum of activity, circumventing resistance, and oral activity to facilitate outpatient treatment. The remainder of this section will give an overview of the various approaches used, classical and novel. Platinum complexes with appended functionalities will be discussed in more detail. 

In our group, a major part of our research is devoted to the design of new anticancer drugs. Our recent efforts towards the discovery of new platinum-, ruthenium- and osmium-based anticancer agents provide the topic for this account and a section is devoted to each metal. We focus on recent results from our lab in the context of other developments and related research in this field (hence our coverage of the field is focused on these areas and is not comprehensive). 

Although the second generation of platinum drugs is less toxic than cisplatin, many appear to be cross-resistant with cisplatin. Requirements which are influencing the search for new generations of active complexes include (1) lower toxicity to normal cells than cisplatin, (2) activity against tumors with acquired cisplatin resistance, (3) activity against a wider spectrum of types of cancer, and (4) oral activity. 

Finally it should be mentioned that the water solubility of the platinum drugs is an important factor in their activity, as it determines the administration protocol. Research towards new compounds is still ongoing, and recently the structures of several readily soluble derivatives, some of them being Pt(IV) compounds, have been described in detail32-34. ... 

H. Harder, then in our laboratory but now at George Washington University, was responsible for these studies. He also checked that the synthesis of precursor molecules for DNA, and the transport of these across membranes was not responsible for the inhibition. He has more recently shown that the ability of the DNA to act as a template for new synthesis is strongly inhibited by the platinum drug. These results can be most reasonably explained by the hypothesis that the anticancer activity of the platinum drugs arises from a primary attack on DNA. The battle to discover the molecular mechanism of action was, therefore, joined on the field of metal complex interactions with DNA, and numerous other laboratories entered the fray. The booty has been rich, embarrasingly so. 

Fokkema E, de Vries EG, Meijer S, Groen HJ. Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients. Cancer Chemother Pharmacol 2000 45(l) 89-92. 

Swiss pharmaceutical company Roche. It is a new platinum anticancer drug, result of a trinuclear platinum coordination complex with chloride and amine ligands. It is active through covalent adducts with DNA inducing apoptosis. 

Platinum drug (JM-216) and blood plasma samples from clinical trial on a new drug... 

Another approach to reducing cisplatin toxicity is to develop new classes of platinum drugs or different routes of their administration. Carboplatin (Figure... 

Figure 1 Structures of platinum drugs that have undergone extensive clinical trials (cisplatin, carboplatin and iproplatin) or are new drugs currently in early clinical trials...

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