Mechanisms of resistance to cisplatin.

A number of changes have been detected in cisplatin-resistant cells, some of which are likely to be directly involved in the mechanism of resistance. The four most cited mechanisms are reduced accumulation, increased glutathione, increased metallothionein, and enhanced DNA repair. Of these mechanisms, reduced accumulation is probably the most common. Detoxification by glutathione or metallothionein may occur in some circumstances, but the evidence is often ambivalent. Enhanced DNA repair has been observed in several cases, but, to date, few cell lines have been adequately investigated for such changes. These observations demonstrate that multiple mechanisms of resistance exist, and often several may occur in the same cell line. To understand the significance of specific mechanisms, many laboratories are attempting to obtain genetic probes. These probes will then be used to clarify the mechanisms of resistance in fresh clinical samples and hopefully will facilitate improvements in therapeutic response.