In vitro Antitumor Activity, Intracellular Accumulation, and DNA Adduct Formation of cis‐[((1R, 2R)‐1,2‐Cyclohexanediamine‐N, N')bis(myristato)] Platinum (II) Suspended in Lipiodol

SM‐11355, cis‐[((1R,2R)‐1,2‐cyclohexanediamine‐N,N')bis(myristato)] platinum (II), is a lipophilic platinum complex under clinical development that targets primary hepatocellular carcinoma using Lipiodol as a carrier. SM‐11355 was compared with cisplatin (CDDP) using an in vitro evaluation system capable of examining the release characteristics and the cytotoxicity of drugs suspended in Lipiodol. SM‐11355 suspended in Lipiodol (SM‐11355/Lipiodol) and CDDP suspended in Lipiodol (CDDP/Lipiodol) showed cytotoxic activity against rat ascites hepatoma AH‐109A cells in a dosedependent manner. Their IC(50) values following 7‐day exposure were 22.3 and 0.40 μg/ml, respectively. Following the subsequent 7‐day exposure, from day 7 to day 14 after preparation of the suspension, SM‐11355/Lipiodol showed an almost equivalent activity, but CDDP/Lipiodol did not show any activity at all. SM‐11355/Lipiodol showed a sustained release into the culture medium over the course of a 14‐day exposure. Following the exposure to CDDP/Lipiodol, the platinum concentration in the medium was at its maximum on the first day and remained constant thereafter. Intracellular platinum uptake and formation of platinum‐DNA adducts were dependent on the release characteristics of each drug suspension. For SM‐11355/Lipiodol, the drug release, intracellular drug uptake, and formation of platinum‐DNA adducts over the course of the subsequent 7‐day exposure were similar to those observed during the first 7 days. DPC, one of the compounds released from SM‐11355/Lipiodol, was taken up by cells and showed formation of platinum‐DNA adducts. Thus, this study suggests that SM‐11355/Lipiodol may release active platinum compound(s) that bind to nuclear DNA and mediate the cytotoxic activity of SM‐11355/Lipiodol.