In vitro cytotoxicity, pharmacokinetics and ex vivo pharmacodynamics of a new platinum compound, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane-2-spiro-1'-cyclopentane]platinum(II)

The in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-1,3-dioxolane-2-spiro-1'-cyclo-pentane]platinum (II) (SKI 2054R) and cisplatin (CDDP) was evaluated against two human stomach adenocarcinoma cell lines (MKN-45 and KATO III) and a human lung adenocarcinoma cell line (PC-14). the in vitro 50% inhibitory concentration (IC50) values of SKI 2.54R and CDDP against MKN-45, KATO III, and PC-14 were 1.21 and 0.51, 2.11 and 0.83, and 2.90 and 0.77 mu g/ml, respectively. The pharma-cokinetic and ex vivo pharmacodynamic studies on SKI 2054R and CDDP were performed in beagle dogs. Equitoxic doses of SKI 2054R and CDDP (7.0 and 3.0 mg/kg, respectively) were administered i.v. bolus to beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the two drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC(0-->infinity)) determined for ultrafiltrable platinum derived from SKI 2054R, as an active component, was 6.61 +/- 2.34 mu g . h/ml (mean+/-S.D.), with an initial half-life of 0.26+/-0.14 h, a terminal half-life of 1.57 +/- 0.71 hour, a total clearance of 17.65 +/- 4.99 ml/min/kg, and a stead-stare volume of distribution of 1.46 +/- 0.11 l/kg. The ex vivo antitumor activity of SKI 2054R was assessed using the ultrafiltrable plasma against MKN-45, KATO III, and PC-14 by tetrazolium-dye (MTT) assay and was compared from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value recorded for SKI 2054R was higher than that noted for CDDP; however statistical difference was not observed between SKI 2054R and CDDP, suggesting that the antitumor activity of SKI 2054R is comparable to that of CDDP. These results suggest that SKI 2.54R is a new platinum complex which is worth being evaluated further.