Developing new anti-cancer drugs: novel targets and methodological problems.

The identification of molecular events relevant in the biology of cancer cells and the possibility of defining the molecular profile of cancer cell lines have radically changed the process of cancer-drug development. Cancer drug discovery relies now mainly on the National Cancer Institute cell line screening program; this screening system allows the selection of compounds with well-defined molecular mechanisms of action by screening them on cell lines characterised at the molecular level and by comparing their cytotoxicity through a computer-based analysis of the response profile. Biologically targeted drugs, which should hit specific molecular or biochemical targets, can be classified by a specific target, such as farnesyltransferase inhibitors, or by general mechanism of action. The clinical development of these new anti-cancer agents presents a significant challenge because clinical studies should comply with the molecular premises and be devised in order to provide the "proof of principle", that is the ability of the drug to interact with and activate or block the molecular target. After a summary of the main features and problems faced in the clinical development of biologically targeted anti-cancer therapies, the pre-clinical and clinical data available for some cell-cycle modulators, signal transduction inhibitors, drugs acting on the mitochondria and proteasome inhibitors will be reviewed.