633 New drug development at the end of the second millenium

Abstract

A limited number of cancer patients can be cured with currently available chemotherapy. Therefore, the search for and subsequent development of more effective and selective agents for cancer remains one of the major challenges in medicine today. Over the last decade our knowledge on the molecular basis of cellular processes like proliferation, differentiation, and apoptosis and their importance in cancer biology and treatment has increased dramatically. Also specific pathways of neoplastic transformation and processes involved in tumour vascularization have been elucidated. Key proteins involved in such processes are currently investigated as possible targets for therapeutic intervention. Among these the E2F transcription factor family, the cyclin dependent kinases, the tumour suppressor gene P53, the enzyme telomerase and others have attracted enormous interest recently. This is illustrated by the rapid growth of mechanism based screens. The availability of large chemicalor natural product collections recently extended by combinatorial libraries and the presence of advanced technology allow high throughput screening of several thousands of compounds per week. Nevertheless, in vitro and in vivo models exhibiting presence or absence of such mechanisms will remain necessary to demonstrate activity at cellular and tumour level. Moreover, by studying drug activity in relation to the level of expression of different targets in tumour cell line panels, the advantages of both random and mechanism based approaches can be combined. Despite several advantages, the human tumour xenograft model in immunodeficient mice or comparable models cannot be used for such first line testing, because of the high costs and relatively large quantities of drug required. By performing limited "rodent only" toxicological research on potential anticancer agents and careful planning of subsequent steps of the drug development process significant unnecessary time loss up to several years between the discovery of a new drug and its ultimate use in clinical medicine can be avoided. This will certainly lead to an even more rapid clinical evaluation of exciting new concepts in the coming years. Several examples of new drugs already under clinical trial will be presented.