Cytotoxicity of cis‐[((1R,2R)‐1,2‐Cyclohexanediamine‐N,N')bis(myristato)]‐platinum (II) Suspended in Lipiodol in a Newly Established Cisplatinresistant 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 crossresistant 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‐II‐E/CDDP. These results suggest that acquired CDDP resistance in H4‐II‐E/CDDP does not influence the cytotoxic activity of SM‐11355/Lipiodol.