Cisplatin

Studies have shown that minor variations in the structure of these ligands can have a profound effect on the antitumour activity and toxicity of platinum complexes. Almost all trans-compounds tested are ineffective, while the cis-counterparts are quite the opposite. It appears that the cis-conformation is required for a complex to be an effective agent. Both cis- and trans- isomers exchange chloride ions for such nucleophilic groups as RS^-, RSCH₃, R¹R²R³N and RNH₂ to form links that can be very stable.

The substitution of ligands of planar platinum(II) compounds, such as DDP ([Pt(NH₃)₂Cl₂]), may follow one of two pathways in aqueous solution. As shown on the right, a chloride ion may be replaced by water to produce a hydrated intermediate, the solvent molecule being subsequently eliminated by an incoming nucleophile. Alternatively, there may be direct replacement of the leaving group without the participation of the solvent. Since cisplatin is administered as an aqeuous solution, it is therefore, essential that ligand substitution be minimised before it reaches the tumour. This is achieved by using isotonic saline which has a relatively high chloride ion concentration, thus keeping the substitution equilibrium to the left:

This ensures that the "inactive" DDP complex will predominate, reducing the amount being converted to the "active" aqua form prior to administration. Once in the body, the high chloride ion concentrations present in blood plasma and extracellular fluid (>100mM), maintains the persistence of the electroneutral complex and prevents any premature activation or unwanted direct ligand substitutions. Being uncharged, the molecule is able to cross cell membranes and thus into cancer cells. The relatively low chloride concentration of the cytosol (intracellular fluid), favours the formation of the active aquated species which goes onto to react with nucleophilic groups. Ligand replacement and chemical reactivity of both isomeric forms of DDP are very similar, however, biological activity is markedly different. The cis isomer has significant cytotoxic properties while the trans isomer does not. Clearly, this must be attributed to the difference in their conformation.

The anticancer properties of cisplatin stem from the relative ease of substitution of the chlorine ligands with nucleophilic species like nucleic acid bases of a DNA strand. Before cisplatin binds to such nucleophiles, it is usually converted to the active form by aquation. Conversion occurs intracellularly as the lower chloride concentrations permit it. The resulting electrophile then goes onto bind to a variety of macromolecules displaying nucleophilic groups, which include DNA. It is now widely accepted that DNA is the primary target of cisplatin. This function is believed to be the largest contribution to its cytotoxicity.

On a simple level, cisplatin forms covalent bonds with nucleophilic sites on guanine present in all DNA. As cisplatin is a bifunctional agent, it is able to bind to two sites in a DNA strand. This results in the formation of inter- and intra- chain cross-linkings which interferes with cellular transcription and replication. Regulatory mechanisms detect the abnormal DNA and so activate a chain of responses to try and correct it. This, ultimately, causes cell death (apoptosis).

The success of cisplatin has been due to a large number of properties. ^¤ Cisplatin,

1. Exhibits a wide spectrum of antitumour activity aginst drug-resistant as well as drug-sensitive tumours;
2. Shows activity against slow-growing tumour as well as rapidly-growing tumours;
3. Shows no strain or species specificity;
4. Exhibits activity against viral-induced, chemical-induced, and transplantable tumours;
5. Affects both solid and disseminated tumours.

The first platinum drugs entered human clinical trials in 1971-1972. The trials culminated in 1978 in the United State with approval for the use of cisplatin in the treatment of testicular and ovarian cancers, and later to bladder cancer. From the definition of chemotherapeutic sensitivity as shown in the table below, a summary of the present clinical utility is given in the second table.

Cisplatin, although active in many tumours, is regularly curative in only one, testicular. The results, however, have been dramatic and, for instance, of approximately 300 patients in one long-term study, 70% were considered as being cured, (see tables below).

A further feature of treatment with cisplatin is the marked synergy shown in combination with a wide variety of other chemotherapeutic agents, such as 5-fluorouracil, cytarabine and bleomycin, which, on a practical level, allows for greater flexibility in the design of drug regimens.

Before we discuss the clinical side of cisplatin and its mode of action, we should first familiarise ourselves with the molecule itself and its general properties.