Clinical perspectives on platinum resistance

The platinum compounds cisplatin and carboplatin are widely used in the treatment of a number of solid malignancies. Although some platinum-sensitive tumours may be cured by combination chemotherapy (e.g. testicular cancer), most will relapse and subsequently prove resistant to platinum compounds. The mechanisms of platinum resistance in patients are still poorly understood. Clearly, when a tumour relapses a long time after successful first-line treatment, there is a high chance that it will still be sensitive to platinum compounds. A number of studies have attempted to assess the role of drug transport, the glutathione system, DNA repair and apoptosis genes in the development of resistance in tumours, but no conclusive evidence is available. Approaches to increasing the potency of platinum therapy (to overcome resistance) have been devised and some have proved to be effective; in particular, intraperitoneal administration of cisplatin has shown superiority over intravenous administration in selected patients with ovarian cancer. The development of drugs and techniques to reduce the adverse effects of platinum chemotherapy has greatly improved their administration. Investigations attempting to modulate platinum activity and toxicity have also been performed. Further investigation of in vivo resistance mechanisms should be valuable in allowing prediction of clinical response to chemotherapy and may identify new treatments with the potential to improve outcomes for patients with a variety of platinum-resistant tumour types.