Contribution of glutathione and MRP-mediated efflux to intracellular oxaliplatin accumulation.

Thirty years of experience using cisplatin in the treatment of cancer have resulted in a growing understanding of its mode of action and led to the successful development of second and third generation analogues. In contrast to the first clinically available compounds cisplatin and carboplatin which exhibit primary resistance against colorectal cancer, oxaliplatin is also effective in this tumor entity. However, some mechanisms associated with acquired resistance against oxaliplatin resemble those reported for cisplatin, including lower intracellular platinum accumulation [1]. Detoxification of platinum complexes by intracellular formation of platinum-glutathione (GSH) adducts and their subsequent efflux via the ABC transporters MRP1 and MRP2 contribute to a decreased accumulation and have been repeatedly suggested as resistance mechanism for cisplatin [2] but have also been the subject of controversy [3]. The present study focuses on oxaliplatin and its detoxification via GSH and MRP-mediated efflux. Electrospray ionization mass spectrometry (ESI-MS) was applied to detect oxaliplatinGSH adducts formed after incubation of oxaliplatin with GSH. Gü83 (Figure 1), a 4aminobenzoic acid derivative recently shown to inhibit MRP1 (IC50 = 1.2 μM) and MRP2 (IC50 = 21.5 μM) [4], was used to investigate the contribution of the transporters to oxaliplatin efflux in oxaliplatin-sensitive and oxaliplatin-resistant ileum carcinoma cells.