Resistance to cisplatin and analogues: mechanisms and potential clinical implications

In view of the important role of cisplatin (CDDP) in cancer chemotherapy, the frequent occurrence of resistance to the drug is a major clinical problem. The main cause for unresponsiveness of a tumor to CDDP is thought to be cellular drug resistance, which may be caused by (1) a decreased uptake of CDDP, (2) an increase in metallothioneins, (3) an increase in glutathione and/or glutathione-S-transferase, (4) increased DNA repair, or (5) increased tolerance to unrepaired lesions in DNA. Several mechanisms may be concomitantly operative. However, almost all data on CDDP resistance are derived from cell lines or experimental animal systems, and it is uncertain whether they are relevant for human tumors. Possible methods for overcoming CDDP resistance in cancer patients include the use of high-dose CDDP or carboplatin or of different formulations of platinum derivatives, the regional administration of CDDP, the inducement of hyperthermia, the depletion of glutathione by buthionine-S-R-sulfoximine (BSO), or the use of platinum analogues. The development of methods to detect and classify CDDP resistance in human tumor samples is urgently required for the development of modalities to overcome resistance.