Mechanism-related circumvention of Cisplatin resistance in human ovarian-carcinoma cells by (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanediacarboxylato)-platinum (ii) monohydrate and modulation of its sensitivity by 12-o-tetradecanoylphorbol-13-acetate

DWA2114R, (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)-platinum( monohydrate, circumvented resistance in cisplatin (DDP)-resistant 2008/C13*5.25 cells to produce some collateral sensitivity. Intracellular platinum levels were not significantly different between parent 2008 and 2008/C13*5.25 cells after exposure to DWA2114R. At equimolar doses, platinum levels were 3.7 +/- 0.4 (SD)-fold (N=4; P<0.01) higher after exposure to DWA2114R than to DDP in 2008/C13*5.25 cells. This suggests that DWA2114R collateral sensitivity was due to its circumvention of impaired platinum accumulation in 2008/C13*5.25 cells, In contrast to our findings that 12-O-tetradecanoylphorbol- 13-acetate (TPA) induced cellular sensitivity to DDP and carboplatin in those cells, TPA did not alter the DWA2114R sensitivity in 2008 cells. Furthermore, it did reduce the DWA211R-resistance of 2008/C13*5.25 cells by a factor of 1.7 +/- 0.2 (SD)-fold (N=4; P<0.05) rather than increase sensitivity. This suggests that TPA sensitization effect was not common to any platinum compounds but was strongly related to their ligands.