In vitro evaluation of platinum, titanium and ruthenium metal complexes in cisplatin-sensitive and -resistant rat ovarian tumors

Abstract

The antitumor activity of eight new metal complexes (three platinum, one titanium, four ruthenium derivatives) was investigated in a cisplatin (DDP)--sensitive (O-342) and a DDP-resistant (O-342/DDP) ovarian tumor line using the bilayer soft-agar assay. A continuous exposure set up at logarithmically spaced concentrations was used to test the drugs; to uncover possible pharmacokinetic features, a short-term exposure was additionally included for selected compounds. DDP served as the reference drug. The following compounds were investigated: 18-crown-6-tetracarboxybis-diammineplatinum(II) (CTDP), cis-aminotrismethylenephosphonato-diammine-platinum(II) (ADP), cis-diamminecyclohexano-aminotrismethylenephosphonato-platin um(II) (DAP), diethoxybis(1-phenylbutane-1,3-dionato)titanium(IV) (DBT, budotitane), trans-imidazolium-bisimidazoletetrachlororuthenate(III) (ICR), trans-indazolium-tetrachlorobisindazoleruthenate(III) (IndCR), cis-triazolium-tetrachlorobis-triazoleruthenate(III) (TCR) and trans-pyrazolium-tetrachlorobispyrazoleruthenate(III) (PCR). Of the new metal complexes, CTDP was the most active compound in O-342, resulting in a percentage of control plating efficiency (+/- SE) of 1 +/- 1, 12 +/- 8 and 40 +/- 21 following continuous exposure to 10, 1 and 0.1 microM, respectively, and was thus comparable to DDP at equimolar concentrations. In the resistant line, 10 microM CTDP reduced colony growth to 18% +/- 8%, whereas an equimolar concentration of DDP effected a reduction to 26% +/- 9%. During short-term exposure. CTDP was inferior to DDP, which may be ascribed to the stability of the bis-dicarboxylate platinum ring system. The titanium compound DBT, in contrast, showed promising effects at its highest concentration (100 microM) during short-term exposure in both lines; at this concentration the activity in O-342/DDP was higher than that in O-342 (7% +/- 7% vs 34% +/- 17% of control plating efficiency at 100 microM). All ruthenium complexes showed higher activity in the resistant line O-342/DDP than in the sensitive counterpart. ICR was the most active compound. Following continuous exposure of O-342/DDP cells to 10 microM ICR, colony growth was reduced to 18% +/- 4% that of controls. Further studies should concentrate on CTDP and ICR for the following reasons; the activity of CTDP was equal to that of DDP at equimolar concentrations during continuous exposure; considering that the in vivo toxicity of DDP was 3-fold that of CTDP, an increase in the therapeutic index of CTDP would be expected. ICR showed the best effect of all ruthenium complexes; it was superior to DDP in the resistant line.