Multi-nuclear platinum drugs: a new paradigm in chemotherapy

The initial report of the therapeutic anticancer properties of a di-nuclear platinum complex in 1988 started a new paradigm in platinum based chemotherapy. Several multi-nuclear platinum complexes have entered clinical trials in recent years, with varying results. This group of charged complexes, consisting of di- and tri-nuclear compounds linked by aliphatic ligands, many with hydrogen bonding functionality, are able to overcome cisplatin and carboplatin resistance in many important human cancer cell lines. The adducts they form with DNA--which are, to some extent, affected by their pre-covalent association--are the reason for their increased cytotoxicity, and are distinctly different from those formed by cisplatin. Multi-nuclear platinum DNA adducts are broadly defined as flexible, non-directional and mainly interstrand cross-links. These complexes are also able to induce conformational changes in DNA, particularly the conversion from B-type to Z- and A-type. While these complexes are much more cytotoxic than cisplatin, they are also highly toxic. The maximum tolerated doses range from 0.006 to 1.1 mg/m(2) which is 10 to 100 fold lower than cisplatin. BBR3464 has shown in vivo activity at its MTD in several pre-clinical and clinical trials; however, recent phase II trials have shown that BBR3464, and other multi-nuclear platinum drugs, did not yield results substantially different from cisplatin, possibly due to their binding and degradation by human plasma proteins. This review will look at the success, and limitations, of multi-nuclear platinum drugs, and discuss their future potential as anti-cancer agents.