Ormaplatin resistance is associated with decreased accumulation of its platinum (II) analogue, dichloro(D,L-trans)1,2-diaminocyclohexaneplatinum (II).
Ormaplatin (also known as tetraplatin) is a platinum-containing analogue which has recently undergone clinical trials. Ormaplatin may undergo conversion to dichloro(D,L-trans)-1,2-diaminocyclohexaneplatinum(II) [P1Cl2(trans-dach)]. The cisplatin-resistant murine lymphoma cell lines E8 and E5, were found to be cross-resistant to ormaplatin and PtCl2(trans-dach). We found an inverse rank correlation between drug resistance and drug accumulation for PtCl2(trans-dach) similar to our previous findings with cisplatin; however, accumulation of ormaplatin in the resistant cells was increased. Ormaplatin cytotoxicity appears to result primarily from extracellular conversion to PtCl2(trans-dach), since ormaplatin cytotoxicity was decreased under conditions where extracellular conversion to PtCl2(trans-dach) was minimised. Co-incubation with different inhibitors of energy metabolism resulted in a 65-70% increase in PtCl2(trans-dach) accumulation in the parental cell line R1.1 and a 113-307% increase in the resistant cell line E5 which suggests that the decrease in accumulation in E5 may be at least partly energy dependent. We conclude from these findings that cross-resistance to ormaplatin is associated with an energy-dependent decreased accumulation of PtCl2(trans-dach) in these cisplatin-resistant cell lines.
Rischin
D
D
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Ling
V
V
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D001386:Azides / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D016190:Carboplatin / Q000633:toxicity; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D007700:Kinetics; D016399:Lymphoma, T-Cell; D051379:Mice; D009944:Organoplatinum Compounds / Q000633:toxicity*; D019810:Sodium Azide; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001386:Azides; D009944:Organoplatinum Compounds; D013438:Sulfhydryl Compounds; D019810:Sodium Azide; D016190:Carboplatin; D002945:Cisplatin; C049777:ormaplatin