New Platinum Agents

Abstract

Compared with most solid tumours in humans, ovarian cancer may be considered a relatively chemosensitive disease. The platinum-based drug, cisplatin, has significantly enhanced long term survival (by more than 10%), though there remains scope for considerable improvement. Carboplatin is equiactive with, but substantially less toxic than, cisplatin (especially in terms of nephrotoxicity, effects on the gastrointestinal tract and neurotoxicity). Long term data are emerging from randomised trials that support the replacement of cisplatin by carboplatin in the first-line treatment of ovarian cancer. Iproplatin is also less toxic than cisplatin, but is more toxic and less active than carboplatin. A further advance in reducing patient morbidity associated with platinum-based chemotherapy may come from the first orally administrable platinum complex, JM216, which has recently been introduced into clinical trials. Current and future platinum drug discovery initiatives should focus on circumventing mechanisms of tumour resistance to cisplatin. Laboratory studies have identified 3 major mechanisms of resistance: reduced drug transport, enhanced intracellular detoxification (through glutathione and/or metallothioneins) and enhanced DNA removal (or tolerance) of platinum-DNA adducts (the long assumed critical lesions leading to cell kill). Platinum complexes based on the 1,2-diaminocyclohexane carrier ligand (such as oxaliplatin and tetraplatin) have recently entered clinical trials, having been shown to circumvent cisplatin resistance in murine leukaemia tumour models. Clinically, they have shown little evidence of activity in cisplatin-resistant disease and appear to cause severe neurotoxicity.