Pharmacological interventions to reduce platinum-induced toxicity

Abstract

Cis-diamminedichloroplatinum (II) or cisplatin is one of the most important anticancer drugs of the last 20 years. The discovery of its antitumoral activity came from a perceptive intuition of Rosenberg (8) studying the effects of an electric field on growing cells. The first clinical results were very promising, but the compound was nearly discarded because of its unusual and very severe kidney toxicity. A major therapeutic advance was the discovery that simple, but adequate hydration of the patient could markedly decrease the nephrotoxicity ofcisplatin without interfering with its anticancer activity. Even better were the results using hypertonic saline as the drug vehicle together with extensive hydration. As a consequence, the possibility of administering cisplatin at higher doses with acceptable toxicity led to more extensive clinical trials in different types of tumours and in a variety of combinations with other anticancer agents. As a result cisplatin is now the drug of choice in multi-drug regimens for the treatment of non-seminomatous testicular cancer and of ovarian cancer and it is useful in the treatment of many other solid turnouts (e.g. head and neck, bladder, lung, sarcomas, lymphomas), usually as part of combination chemotherapy. Cisplatin in water reacts immediately by exchange of the labile chlorides for water or hydroxyl ions. The aquation reaction of cisplatin is highly dependent on chloride levels. In plasma, or in high chloride fluids, the neutral dichloro complex will predominate whereas intracellularly, where the chloride ion concentrations are very low, the aquated species will predominate. The aquated complexes are very reactive and are easily replaced by a variety of nucleophiles. The cisplatin antitumour effect is mediated by reaction with DNA, the N-7 position of guanine being the most reactive site. There is an initial formation of mono-adducts and then a rapid intra-stand cross-linking, responsible for the cisplatin cytotoxicity. These reactions are merely mentioned here because of their importance in understanding the possible mechanism of action of some ‘chemoprotectors’. It ought also to be mentioned here that Carboplatin, a less toxic analog of cisplatin now on the market, forms the same platinum-DNA adducts as cisplatin but with different kinetics of DNA binding. The full anticancer activity of cisplatin and Carboplatin have yet to be explored if and when their severe dose-limiting toxicity can be overcome. Nephrotoxicity is the doselimiting toxicity of cisplatin at conventional doses (up to 120 mg/m’) and neurotoxicity is the toxicity limitation at high doses (160-200 mg/m*) (Table 1). The dose-limiting toxicity of Carboplatin, althou,gh less nephrotoxic than cisplatin, is myelosuppression.