Introduction Antitumor Activity of Cisplatin

Platinum compounds constitute a discrete class of chemotherapeutics, which are now widely used in the clinic as anti-tumor and anti-viral agents. The interest in platinum chemotherapeutics has its origin in the 1960s, with the serendipitous discovery by Rosenberg of the inhibition of division of bacterial cells by platinum complexes.1 The first platinum anti-cancer drug introduced in the clinic is cisplatin [ci's-diamminedichloroplatinum(II)]. This very simple and purely inorganic molecule (Figure 25.1) was first synthesized in 1844 and at that time was called Peyrone's chloride.

The ammonia ligands in this platinum(II) molecule represent non-leaving groups whereas the chlorides can be replaced by other ligands (nucleophiles). Hence, cisplatin belongs to the class of bifunctional reactants. In spite of its simplicity it is one of the most potent drugs available for anti-cancer chemo-therapy.2,3 Cisplatin is highly effective for the treatment of testicular and ovarian cancer and is used in combination regimens for a variety of other carcinomas, including bladder, small lung tumors and those of the head and neck. However, cisplatin toxicity in tumor cells is coupled with several drawbacks.2

Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine Edited by Gielen and Tiekink © 2005 John Wiley & Sons, Ltd

Figure 25.1 Platinum complexes used clinically

Its applicability is still limited to a relatively narrow range of tumors. Some tumors have natural resistance to cisplatin, while others develop resistance after initial treatment. Cisplatin also has limited solubility in aqueous solution and is administered intravenously. There are also significant problems in terms of inducing severe side-effects2 (especially kidney damage, vomiting/nausea, neurotoxicity and emetogenesis).

The limitations associated with the clinical use of cisplatin prompted a search for more effective and less toxic alternative platinum anti-tumor agents. This effort led to the synthesis of thousands of platinum complexes which were evaluated as anti-tumor agents and tested in cancer cells, but only a few reached clinical trials and most of them have already been rejected. Those which have achieved routine clinical use and have been approved for clinical administration, together with cisplatin, are its direct analogues (Figure 25.1), namely carboplatin [cis-diamminecyclobutanedicarboxylatoplatinum(II)], oxaliplatin {[(1R,2R-diamminocyclohexane)oxalatoplatinum(II)] (1,2-diaminocyclohexane = DACH)} and nedaplatin [ci's-diammineglycolatoplatinum(II)].

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