Cisplatin clinical properties

This chapter describes the clinical properties of cisplatin, and of its analogues that have undergone extensive clinical trials (particularly carboplatin), platinum chemistry relating to mechanism of action, the mechanisms of tumour resistance to cisplatin and their circumvention. 

Cisplatin was introduced into clinical practice in 1971 (only some five years after the initial discovery of its cell-killing properties), and the less toxic analogue, carboplatin, in 1981. To date, carboplatin is the only platinum analogue to have received worldwide registration. Comparative clinical properties of cisplatin and carboplatin are summarised in Table 1. 

Table 1 Comparative clinical properties of cisplatin and carboplatin...

The first report on the anticancer properties of ruthenium was published in 1976 when the Ru(III) compound /ac-[RuC13(NH3)3] (Fig. 11) was found to induce filamentous growth of Escherichia coli at concentrations comparable to those at which cisplatin generates similar effects (49). This Ru(III) complex and related compounds such as cis-[RuCl2(NH3)4]Cl illustrated the potential anticancer activity of ruthenium complexes, but insolubility prevented further pharmacological use. Since these initial studies, other Ru(III) complexes have been studied for potential anticancer activity, and two compounds, NAMI-A (50) and KP1019 (51), are currently undergoing clinical trials. Remarkably,... 

The chemotherapeutic agent d.v-diammincdichloroplatinum(II), cis-DDP, or cisplatin, can form covalent adducts with many cellular macromolecules, but there is convincing evidence that its cytotoxic properties are a consequence of bifunctional-DNA adduct formation [ 1 ] [2]. Platinum binds to the N(7) position of purine nucleotides, resulting predominantly in 1,2-d(GpG) and l,2-d(ApG) intrastrand cross-links, but also in l,3-d(GpNpG) intrastrand, interstrand and protein-DNA cross-links [3][4], The 1,2-intrastrand cross-links, which comprise 90% of the DNA adducts, are not formed by the clinically inactive trans-DDP because of geometric constraints, and attention has therefore focused on these adducts as the active lesions in the anticancer activity of the drug. 

After the serendipitous discovery of the antitumor properties of cisplatin (m-diaminedichloro-platinum), much effort has been devoted to finding other anticancer metal agents, and several Sn, Ti, Zr, and Hf /3-diketonates have been proven to possess interesting biological activity. For example, budotitane ((EtO)2Ti(bzac)2) was the first non-Pt metal complex to reach clinical trials as a potential anticancer agent.11-15... 

As mentioned in the introduction, metallocene-type complexes based on the early transition metals were evaluated as anticancer compounds shortly after the discovery of cisplatin. While the biological activity of each of the metallocene dihalides is unique, titanocene dichloride 7 has been the subject of a number of studies and even entered clinical evaluation, although evaluation was discontinued (not due to its anti-proliferative properties), principally due to formulation problems, despite showing superior activity to certain cancers than other established drugs. This class of compound continues to be modified and studied for anticancer activity, for example, the titanocene-type derivative of tamoxifen 1, described above, and other developments described below. 

More importantly the amines are also responsible for activity in cisplatin-resistant cells (Figure 2.4). This has important clinical implications and the demonstration of the lack of cross resistance in 1,2-diamino-cyclohexane complexes [51] is responsible for much of the interest in developing these particular complexes. This ligand is also of interest from a mechanistic point of view because of the demonstration that different stereoisomers also have different biological properties. 

---