Modulation of cis-diamminedichloroplatinum (II) accumulation and cytotoxicity by spermine in sensitive and resistant human ovarian carcinoma cells

The effect of spermine (Sp), a natural polycationic amine, on cisplatin (CDDP) sensitivity and accumulation of a human ovarian CDDP-sensitive cell line (2008) and its resistant variant (C13*) was investigated. Survival was also studied. The C13* cells were approximately 20-fold resistant to CDDP, yet were found to be lust as sensitive to Sp as 2008 cells. When Sp was concurrently added with CDDP to the colony-forming assay, the IC50 dose was approximately 3-fold lower than that of CDDP alone. This decrease was the result of a synergistic interaction, as assessed by median effect analysis. The incubation of cells with the approximate IC50 dose of Sp for 1-8 h indicated that this synergism could be due to stimulation of CDDP accumulation, showing maximal uptake after 4 h of Sp exposure. This stimulation may be the result of a modulation of cellular membrane permeability by Sp, as assessed by the accumulation of [H-3]mannitol. Exposure to Sp concentrations active on CDDP uptake also significantly increased [H-3]mannitol accumulation in both cell lines. The triamine spermidine (Spd) did not significantly affect either the sensitivity of the two cell lines or CDDP and [H-3]mannitol accumulation. These results suggest that Sp is a positive modulator of CDDP uptake, and thus of its cytotoxicity, even in resistant cells, where the phenotype is partly due to a CDDP accumulation defect. (C) 1997 Published by Elsevier Science Ltd.