Article
Novel Titanocene Anti-Cancer Drugs
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Published: | March 20, 2006 |
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Outline
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Titanocene dichloride (Cp2TiCl2) shows significant activity against a variety of human cancer cell lines, overcomes the resistance against cis-platin and reached two clinical Phase II studies against renal cell and metastatic breast cancer. But Cp2TiCl2 failed in these studies due to a lack in anti-proliferative activity and also demonstrated severe renal and liver toxicities at high concentrations.
The aim of our research is to synthesise suitably substituted titanocenes and ansa-titanocenes in order to control the physiological uptake of the titanocenes and to overcome the toxicity effects exhibited by titanocene dichloride. In addition we model the titanocene-DNA interaction leading finally to apoptosis.
Ansa-titanocene dichlorides are obtained by reductive dimerisation of substituted aryl fulvenes with TiCl2, while un-bridged titanocenes are available from fulvenes through the addition of lithium hydride or aryl lithium ([Ref. 1], [Ref. 2], [Ref. 3], [Ref. 4], [Ref. 5]).
We investigate the cytotoxic activity of all titanocenes on LLC-PK pig kidney carcinoma cells and that of selected titanocenes on a 36 cell-line panel in vitro. Results show that our most effective titanocene has a significantly higher activity than Cp2TiCl2 itself. Recently, our best titanocenes have successfully finished pre-clinical animal studies (EAT and Caki-1 in mice) as well as clinical ex vivo tests involving a variety of explanted human tumours.
Acknowledgement: The authors want to acknowledge financial support from COST, HEA and SFI.
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