THEORETICAL AND PRACTICAL CONSIDERATIONS IN SCREENING STRATEGIES FOR DIFFERENTIATION AGENTS

This paper reviews strategies for identification of new compounds with differentiation inducing activity. The primary objective is to discri minate 'lead' compounds with novel mechanisms of action. Complementary to this is the need to generate a taxonomy of known compounds, identi fying those with similar mechanisms, preferably in a way that provides clues as to the nature of those mechanisms. Experimental data suggest that the methods to do this are already to hand and that some existin g search strategies are readily adapted to these objectives. The princ ipal property required of the screen is that distinct mechanisms of in duction produce different outcomes. Response patterns can thus be used to group drugs with similar mechanisms and hence identify novel activ ities. To be successful, such patterns have to be relatively insensiti ve to potency (so that agents with the same mechanism but different po tency are classed together). Two strategies to achieve mechanism-sensi tive response patterns are outlined, one based on the varied response capacities of multiple target cell types and another exploiting drug i nteraction patterns. With the former, the principle exploited is that the differences in the panel cells' capacities to respond depend on th e components and assembly of their signal transduction and effector me chanisms for differentiation. With the latter, it is the varied and co mplex ways in which the components of the intracellular mechanism are assembled which provides distinctive interaction patterns, depending u pon which components are the molecular targets of a particular pair of drugs. Pattern generation, analysis and optimisation of efficacy and cost/benefit are also discussed. Differentiation end-points are diffic ult to assess and cell number/mass may be more appropriate to high thr oughput designs. The problems of discriminating growth arrest due to d ifferentiation, from other antiproliferative or simply cytotoxic effec ts are therefore considered and suggestions made for feasibility studi es of these approaches.