Abstract
Development of resistance to cytotoxic agents is a major limitation to their clinical use. Novel compounds are synthesized with a view to develop non-cross-resistant, less toxic and more potent activity. The detection of the anti-tumour properties of the inorganic compound cisplatin stimulated a broad search for other metal-containing complexes. Titanocene dichloride was synthesized on this basis and has shown potent anti-neoplastic activity in experimental animals. We have examined the in vitro activity of titanocene dichloride in two pairs of platinum-sensitive and resistant human ovarian carcinoma cell lines, A2780/2780CP and CH1/CH1cisR, and in mutated p53- and bcl-2-transfected clones of A2780 cells. A time- and concentration-dependent anti-proliferative effect was observed in all cell lines treated with titanocene dichloride. The drug was found to significantly overcome platinum resistance in the 2780CP and the CH1 cisR cell lines and in the bcl-2 and the mutant p53 transfectants of A2780 cells. Titanocene dichloride induced a block in late S/early G2 phase of the cell cycle; however apoptotic cell death occurred from any phase of cycle. Titanium-DNA adducts were detected in A2780 cells treated with titanocene dichloride using atomic absorption spectrometry, suggesting that DNA may be a target for this drug. In agreement with this finding, p53 accumulated rapidly in drug-treated A2780 cells, indicative of a role for titanocene dichloride as a DNA-damaging agent. We have also performed studies to determine whether titanocene dichloride could demonstrate synergy with other cytotoxic agents in vitro. Isobologram analysis of cytotoxicity data obtained suggests that the combination of titanocene dichloride and 5-fluorouracil (5-FU) is synergistic. The potent in vivo anti-tumour activity of this compound, supported by the encouraging results from two phase I clinical trials, suggests that titanocene dichloride could be a promising novel chemotherapeutic agent.
Highlights
In order to determine whether titanocene dichloride confers antiproliferative properties in vitro, A2780 ovarian carcinoma cells were treated for 2 h with various drug concentrations (1 x 1042 x 10- M), and cell viability was assessed 48 h later by MTT conversion assays
The above results suggest that titanocene dichloride confers antiproliferative properties in vitro, the drug concentrations necessary to inhibit cell growth are significantly higher than those of cisplatin
The in vivo anti-tumour activity of the organometallic compound titanocene dichloride has been previously documented in experimental animals, little is known about its mode of action
Summary
The human ovarian carcinoma cell line A2780 and the acquired platinum-resistant 2780CP (Behrens et al, 1987) were kindly provided by Dr J Plumb (University of Glasgow, Glasgow, UK). These lines were continuously maintained in RPMI medium supplemented with 10% fetal calf sesum (FCS) (Flow, UK), 1% glutamine and 1% penicillin/streptomycin. The formulation was supplied as a freeze-dried powder in vials containing 50 mg of drug. It was stored at 4°C, protected from light.
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