CROSS-RESISTANCE BETWEEN CISPLATIN AND ANTIMONY IN A HUMAN OVARIAN-CARCINOMA CELL-LINE

The metal compound cisplatin (DDP) is a widely used anticancer agent b ut naturally occurring and acquired resistance to DDP limits its effec tiveness, Resistance is associated with a decreased accumulation of DD P and increased levels of glutathione and metallothioneins. Such chang es also serve as protective and detoxification mechanisms for other me tal salts in prokaryotes and lower eukaryotes, The aim of this study w as to find metal salts for which the cross-resistance profile was the same as for DDP in sublines of the parental 2008 human ovarian carcino ma cells selected with either DDP (2008/C135.25) or CdCl2 and ZnCl2 ( 2008/MT), Among the metal salts tested the resistance profile of triva lent antimony most closely resembled that of DDP, DDP-selected cells w ere 15-fold resistant to DDP and 4.4-fold cross-resistant to antimony potassium tartrate, whereas of the cations tested (Cd2+, Zn2+, Ni,(2+) and Co2+) Cross-resistance was observed only for Cd2+ (2.4-fold), Whe n 2008 cells were selected for resistance to antimony (6.6-fold) they were found to be 16-fold cross-resistant to DDP, Accumulation of the D DP analogue cis-[H-3]dichloro(ethylenediamine)platinum(II) was 59% low er in the DDP-selected subline and 48% lower in the antimony-selected variant than in the parental cell line, We conclude from the mutual cr oss-resistance to DDP and antimony potassium tartrate and from the imp aired uptake of [H-3]DEP in both the DDP and antimony-selected variant s that DDP and antimony share a common mechanism of resistance, The si gnificance of this observation lies in the fact that several evolution arily conserved mechanisms for antimony detoxification are already kno wn in lower organisms which may point the way to identification of add itional DDP resistance mechanisms in mammalian cells.