ANTIPROLIFERATIVE ACTIVITY AND MECHANISM OF ACTION OF TITANOCENE DICHLORIDE

Development of resistance to cytotoxic agents is a major limitation to their clinical use. Novel compounds are synthesized with a view to de velop non-cross-resistant, less toxic and more potent activity. The de tection of the anti-tumour properties of the inorganic compound cispla tin stimulated a broad search for other metal-containing complexes. Ti tanocene dichloride was synthesized on this basis and has shown potent anti-neoplastic activity in experimental animals, We have examined th e in vitro activity of titanocene dichloride in two pairs of platinum- sensitive and resistant human ovarian carcinoma cell lines, A2780/2780 CP and CH1/CH1cisR, and in mutated p53- and bcl-2-transfected clones o f A2780 cells. A time-and concentration-dependent anti-proliferative e ffect was observed in ail cell lines treated with titanocene dichlorid e, 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 mutan t p53 transfectants of A2780 cells. Titanocene dichloride induced a bl ock in late S/early G(2) phase of the cell cycle; however apoptotic ce ll death occurred from any phase of cycle. Titanium-DNA adducts were d etected 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 a s a DNA-damaging agent. We have also performed studies to determine wh ether titanocene dichloride could demonstrate synergy with other cytot oxic agents in vitro. Isobologram analysis of cytotoxicity data obtain ed suggests that the combination of titanocene dichloride and 5-fluoro uracil (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 prom ising novel chemotherapeutic agent.