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

  • Original Articles
  • Platinum, Titanium, Ruthenium, Metal Complexes, Ovarian Tumors
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Summary

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-diammineplatinum(II) (ADP),cis-diamminecyclohexano-aminotrismethylenephosphonato-platinum(II) (DAP), diethoxybis(1-phenylbutane-1,3-dionato)titanium(IV) (DBT, budotitane),trans-imidazolium-bisimidazoletetrachlororuthenate(III) (ICR),trans-indazolium-tetrachlorobisindazoleruthenate(III) (IndCR),cis-triazolium-tetrachlorobistriazoleruthenate(III) (TCR) andtrans-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 μm, respectively, and was thus comparable to DDP at equimolar concentrations. In the resistant line, 10 μm 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 μm) 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 μm). 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 μm 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.

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  1. Institute of Toxicology and Chemotherapy, German Cancer Research Center, Im Neuenheimer Feld 280, W-6900, Heidelberg, Federal Republic of Germany

    S. Frühauf & W. J. Zeller

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Frühauf, S., Zeller, W.J. In vitro evaluation of platinum, titanium and ruthenium metal complexes in cisplatin-sensitive and-resistant rat ovarian tumors. Cancer Chemother. Pharmacol. 27, 301–307 (1991). https://doi.org/10.1007/BF00685116

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