The
metallocene dihalides are a relatively new class of small, hydrophobic organometallic
anticancer agents that exhibit antitumour properties against numerous cell lines including
leukemias P388 and L1210, colon 38 and Lewis lung
carcinomas,
B16 melanoma, solid and fluid Ehrlich
ascites tumours and several human colon and lung
carcinomas transplanted into athymic mice.
Titanocene dichloride 1 has been the most widely studied
metallocene and the
drug is currently in phase II clinical trials. Formation of
metallocene-
DNA complexes has been implicated in the mechanism of antitumour properties of the
metallocenes, as both
titanocene dichloride 1 and
vanadocene dichloride 2 inhibit
DNA and
RNA synthesis, and
titanium and
vanadium accumulate in
nucleic acid-rich regions of tumour cells. However, in contrast to the well characterized
platinum-based anticancer drugs, the active species responsible for antitumour activity in vivo has not been identified and the mechanism whereby irreparable DNA damage and/or structural modification of
DNA or other cellular targets occurs is poorly understood. This review will focus on recent studies that have been carried out in order to identify the biologically active species and more fully understand the molecular level mechanism of action of the
metallocene dihalides. Studies with
nucleotides,
oligonucleotides,
DNA and
proteins including topoisomerases,
protein kinase C and
transferrin have provided important insight into potential cellular transport mechanisms and the interaction of
metallocenes with biomolecular targets. New structure activity studies including the design of hydrolytically stable
metallocenes and the preparation of highly water soluble
amino acid analogues have not led to improved anticancer activity of
titanocene dichloride 1. The vastly different chemical and hydrolytic stability of each of the
metallocenes points to a unique mechanism of action of each
metallocene in vivo.