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Preclinical models in cancer drug discovery and development

      The continued clinical need for new cancer medicines and recent advances in molecular pathology have resulted in unprecedented levels of activity in both the academic and commercial drug-development communities. Methods such as high-throughput genomic and proteomic analyses, and high-throughput compound screening and structure-based drug design, are identifying a large number of drug targets and the molecules that act on these. However, the complexities of the cell and intact organisms are such that it is not yet possible to progress directly from cell-free, or indeed in vitro cell culture-based, assays to clinical trials. Hence preclinical models of human cancer are needed to prioritise and select potential drug candidates for investigations in man. There are at least three important reasons for this circumstance. First, while patients are open, to an astonishing degree, to receiving investigational interventions, ethical approaches that would avoid exploiting their altruism should help provide some basis for at least the possibility of value and the likelihood of safety for the individual while participating in such clinical research. Unfortunately, no cell-free or cell culture-based assay can yet provide this information. Secondly, a molecule active in a cell-free or purely cell-culture system is not a ‘drug’, the historical distinction resting in that the fact that bona fide drugs possess the capacity for ‘pharmacological action at a distance’ across the boundaries of the route of administration, stability in the circulation, metabolising systems, and elimination routes encountered in organisms. Thirdly, from a pragmatic and economically important point of view to those who must apportion resources for drug discovery, no ultimately successful cancer treatment used today is without robust activity in at least some model of cancer treatment.
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