PROGRESS IN PLATINUM-DERIVED DRUG DEVELOPMENT

This contribution summarizes the current state of platinum anticancer drug development. A brief update of the status of clinical trials of platinum formulations, as well as new molecular entities, is first given. This is followed by a description of the structures and properties of the leading candidates for further drug development. Emphasis is placed on structural innovation and new chemotypes with the potential for complementarity with the clinically used drugs. The structures are demonstrated in the context of molecular approaches to addressing the three principal determinants of platinum cytotoxicity -the extent of destabilizing metabolic interactions, cellular accumulation and the structure and quantity of Pt-DNA adducts. The medium- to long-term prognosis for cancer drug therapy is that it will consist of a combination of the newer targeted drugs that prove successful and newer improved cytotoxics. Avenues to explore rational preclinical combinations based on the recent understanding of platinum drug clinical efficacy and resistance are suggested.