Cytotoxicity of cis-[((1R,2R)-1,2-cyclohexanediamine-N,N′)bis(myristato)]-platinum (II) suspended in lipiodol in a newly established cisplatin-resistant rat hepatoma cell line

The cytotoxic activity of cis-[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)]platinum (II) (SM-11355) was evaluated in a cisplatin (CDDP)-resistant tumor cell line, and compared with that of CDDP. H4-II-E/CDDP with acquired resistance to CDDP was established by continuous exposure of a rat hepatic tumor line, H4-II-E, to increasing concentrations of CDDP over 12 months. Compared with the parental cell line, this cell line exhibited an 8.8-fold increase in resistance to CDDP and was not cross-resistant to 1,2-diaminocyclohexane platinum (II) dichloride (DPC). There were no differences in sensitivity to six non-platinum antitumor drugs between H4-II-E and H4-II-E/CDDP, which suggests that H4-II-E/CDDP is not multidrug-resistant. Intracellular platinum accumulation and the formation of a platinum-DNA adduct following CDDP exposure were significantly reduced in H4-II-E/CDDP compared to the parental cell line. The acquired CDDP resistance in H4-II-E/CDDP appeared to be predominantly due to reduced CDDP uptake. H4-II-E/ CDDP was also resistant to CDDP suspended in Lipiodol (CDDP/Lipiodol), but was not cross-resistant to SM-11355 suspended in Lipiodol (SM-11355/Lipiodol). Also, there were no differences in intracellular platinum accumulation or the formation of platinum-DNA adducts after SM-11355/Lipiodol exposure between H4-II-E and H4-11-E/CDDP. These results suggest that acquired CDDP resistance in H4-II-E/CDDP does not influence the cytotoxic activity of SM-11355/Lipiodol.