A better platinum-based anticancer drug yet to come?

Abstract

In attempts to overcome the drawbacks of cisplatin - severe toxicity, drug resistance and poor oral bioavailability - the development of platinum-based drugs has progressed from carboplatin and oxaliplatin to the newest generation of drugs, such as satraplatin, picoplatin and the multinuclear platinum complex BBR3464 (triplatin). Despite encouraging preclinical in vitro and in vivo results, outcomes of clinical trials of these coordination complexes remained below expectations. Biased rationale underlying the drug design along with in vitro and in vivo preclinical tests with inadequate predictive power seem to have eventually resulted in the selection of drug candidates of limited clinical activity. The nature of the active species generated in vivo, uptake, efflux, intracellular trafficking and detailed mechanisms involved in chemoresistance of platinum drugs in vivo are topics that need further investigation to provide clues for the rational formulation of new drugs. Insufficient diffusion in tumor tissues is likely to constitute an important limiting step in the treatment of solid tumors with platinum compounds. Preclinical assays with improved predictive power for the clinical outcome of the compounds should be based on more representative tumor models, such as resistant primary cancer cell lines, spheroids and orthotopic xenograft models, respectively. Finally, use of new pharmaceutical formulations and bifunctional complexes, as well as their selection by decisive preclinical tests, are expected to result in the generation of platinum-based anticancer drugs with the potential to achieve clinical activity even in multidrug-resistant tumors.