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 2054R 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 micrograms/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 dose 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-tine curve (AUC(0)--> infinity) determined for ultrafiltrable
platinum derived from
SKI 2054R, as an active component was 6.61 +/- 2.34 micrograms . 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 steady-state 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 with that of CDDP using the antitumor index (ATI) determined 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 2054R is a new
platinum complex which is worth being evaluated further.